Salts, co-crystals, and polymorphs of an anxiolytic compound

ABSTRACT

The present invention provides amorphous arid crystalline forms of 1-ethyl-6-(indan-2-ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4-one (compound 1), and salts, co-crystals, and pharmaceutical compositions thereof. The invention also provides methods of treating and/or preventing a disease, such as a central nervous system disease (e.g., an anxiety disorder), using the amorphous and crystalline forms, and salts, co-crystals, and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 8,293,737, the entirety of which is incorporated herein byreference, describes certain 1,8-naphthyridin-4(1H)-one compounds whichare useful as anxiolytic agents. Such compounds include1-ethyl-6-(indan-2-ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4-one(compound 1).

Compound 1 possesses anxiolytic activity without sedative side effectsand therefore represents an attractive alternative to the1,4-benzodiazepine class of anxiolytics such as diazepam.

SUMMARY OF THE INVENTION

It has now been found that salt forms and polymorphs described herein,and compositions thereof, are useful as therapeutic agents and in thepreparation of pharmaceutical compositions and exhibit desirablecharacteristics for such purposes. In general, these salt forms andpolymorphs, and pharmaceutically acceptable compositions thereof, areuseful for treating or lessening the severity of a variety of diseasesor disorders described herein (e.g., an anxiety disorder).

Provided herein are various crystalline forms of compound 1. In someembodiments, the crystalline form of compound 1 is substantiallyanhydrous. In some embodiments, the crystalline form of compound 1 is asolvate (e.g., a hydrate). In some embodiments, the crystalline form ofcompound 1 is a hydrate. In some embodiments, the crystalline form ofcompound 1 is Form C in some embodiments, the crystalline from ofcompound 1 is Form D in some embodiments, the crystalline form ofcompound 1 is Form B in some embodiments, the crystalline form ofcompound 1 is Form F. In some embodiments, the crystalline form ofcompound 1 is Form G. In some embodiments, the crystalline form ofcompound 1 is Form H. In some embodiments, the crystalline form ofcompound 1 is Form I. In some embodiments, the crystalline form ofcompound 1 is Form J. In some embodiments, the crystalline form ofcompound 1 is Form K. In some embodiments, the crystalline form ofcompound 1 is Form L. In some embodiments, the crystalline form ofcompound 1 is Form M.

In some embodiments, provided herein is a pharmaceutically acceptablesalt of compound 1, wherein the pharmaceutically acceptable salt is anacid addition salt. In some embodiments, the salt is amorphous. In someembodiments, the salt is crystalline. In some embodiments, the salt issubstantially anhydrous. In some embodiments, the salt is a solvate(e.g., a hydrate). In some embodiments, provided herein are fumarate,L-malate, D-malate, succinate, maleate, thiocyanate, oxalate, benzoate,2-oxoglutarate, and tartrate salts of compound 1. In some embodiments,provided herein are fumaric acid, L-malic acid, D-malic acid, succinicacid, maleic acid, hydrogen thiocyanate, oxalic acid, benzoic acid,2-oxoglutaric acid, and tartaric acidco-crystals of compound 1.

In another aspect, the present invention provides additional solidforms, such as Form FUM-P3, Form FUM-P4, Form MLA-P3, Form MLA-P4, FormSUC-P3, Form SUC-P4, Form SUC-P5, Form MLE-P4, and Form MLE-P6. In someembodiments, Form FUM-P3 is a fumarate salt of compound 1. In someembodiments, Form FUM-P4 is a fumarate salt of compound 1. In someembodiments, Form FUM-P5 is a fumarate salt of compound 1. In someembodiments, Form MLA-P3 is an L-malate salt of compound 1. In someembodiments, Form MLA-P4 is an L-malate salt of compound 1. In someembodiments, Form SUC-P3 is a succinate salt of compound 1. In someembodiments, Form SUC-P4 is a succinate salt of compound 1. In someembodiments, Form MLE-P4 is a maleate salt of compound 1. In someembodiments, Form MLE-P6 is a maleate salt of compound 1.

The present invention also provides co-crystals formed from compound 1and an additional compound. In certain embodiments, the co-crystal is acomplex of compound 1 and the additional compound. In certainembodiments, the additional compound is a coformer, such as a solventand an additional pharmaceutical agent (e.g., an additional therapeuticor prophylactic agent described herein). In some embodiments, FormFUM-P3 is a co-crystal of compound 1 and an additional compound. In someembodiments, Form FUM-P4 is a co-crystal of compound 1 and an additionalcompound. In some embodiments, Form MLA-P3 is a co-crystal of compound 1and an additional compound. In some embodiments, Form MLA-P4 is aco-crystal of compound 1 and an additional compound. In someembodiments, Form SUC-P3 is a co-crystal of compound 1 and an additionalcompound. In some embodiments, Form SUC-P4 is a co-crystal of compound 1and an additional compound. In some embodiments, Form SUC-P5 is aco-crystal of compound 1 and an additional compound. In someembodiments, Form MLE-P4 is a co-crystal of compound 1 and an additionalcompound. In some embodiments, Form MLE-P6 is a co-crystal of compound 1and an additional compound.

The present invention also provides amorphous forms of compound 1. Incertain embodiments, the amorphous form is Form A.

In some embodiments, provided herein are pharmaceutical compositionscomprising a crystalline form of compound 1 and optionally an additionalingredient selected from pharmaceutically acceptable carriers, diluents,and excipients. In some embodiments, the pharmaceutical compositioncomprises Form C of compound 1. In some embodiments, the pharmaceuticalcomposition comprises Form D of compound 1. In some embodiments, thepharmaceutical composition comprises Form E of compound 1. In someembodiments, the pharmaceutical composition comprises Form F ofcompound 1. In some embodiments, the pharmaceutical compositioncomprises Form G of compound 1. In some embodiments, the pharmaceuticalcomposition comprises Form H of compound 1. In some embodiments, thepharmaceutical composition comprises Form I of compound 1. In someembodiments, the pharmaceutical composition comprises Form J ofcompound 1. In some embodiments, the pharmaceutical compositioncomprises Form K of compound 1. In some embodiments, the pharmaceuticalcomposition comprises Form L of compound 1. In some embodiments, thepharmaceutical composition comprises Form M of compound 1. In someembodiments, provided herein is a pharmaceutical composition comprisinga fumarate, L-malate, D-malate, succinate, maleate, thiocyanate,oxalate, benzoate, 2-oxoglutarate, or tartrate salt of compound 1, andoptionally an additional ingredient selected from pharmaceuticallyacceptable carriers, diluents, and excipients. In some embodiments, thepharmaceutical composition comprises Form FUM-P3. In some embodiments,the pharmaceutical composition includes Form FUM-P4. In someembodiments, the pharmaceutical composition comprises Form MLA-P4. Insome embodiments, the pharmaceutical composition comprises Form SUC-P3.In some embodiments, the pharmaceutical composition comprises FormMLE-P4. In some embodiments, the pharmaceutical composition comprisesForm MLE-P6.

In some embodiments, provided herein are pharmaceutical compositionscomprising an amorphous form of compound 1 and optionally an additionalingredient selected from pharmaceutically acceptable carriers, diluents,and excipients. In some embodiments, the pharmaceutical compositioncomprises Form A.

Also provided herein are methods of preventing and/or treating variousdiseases, disorders, or conditions comprising administering to a subjecta pharmaceutical composition described herein. Pharmaceuticalcompositions and uses described herein comprises one or more of thepolymorphs (e.g., Form C to Form M) or salts (e.g., fumarate, L-malate,D-malate, succinate, maleate, thiocyanate, oxalate, benzoate,2-oxoglutarate, or tartrate salt) of Compound 1 described herein.

Definitions

The following definitions are more general terms used throughout thepresent application:

The term “solvate” refers to forms of a compound (e.g., compound 1) thatare associated with a solvent, usually by a solvolysis reaction. Thisphysical association may include hydrogen bonding. Conventional solventsinclude water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether,and the like. In certain embodiments, solvates are formed using Class 3solvent(s). Categories of solvents are defined in, for example, theInternational Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH), “Impurities:Guidelines for Residual Solvents, Q3C(R3), (November 2005). A compoundmay be prepared, e.g., in crystalline form, and may be solvated.Suitable solvates include pharmaceutically acceptable solvates andfurther include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances, the solvate will be capable ofisolation, for example, when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. “Solvate”encompasses both solution-phase and isolable solvates. Representativesolvates include hydrates, ethanolates, and methanolates.

The term “hydrate,” refers to a compound (e.g., compound 1) which isassociated with water. Typically, the number of the water moleculescontained in a hydrate of a compound is in a definite ratio to thenumber of the compound molecules in the hydrate. Hydrates include bothstoichiometric hydrates and non-stoichiometric hydrates. Therefore, ahydrate of a compound may be represented, for example, by the generalformula R.xH₂O, wherein R is the compound and wherein x is a numbergreater than 0. A given compound may form more than one type ofhydrates, including, e.g., monohydrates (stoichiometric, x is 1), lowerhydrates (non-stoichiometric, x is a number greater than 0 and smallerthan 1, e.g., hemihydrates (R.0.5H₂O)), and polyhydrates(non-stoichiometric, x is a number greater than 1, e.g., dihydrates(R.2H₂O) and hexahydrates (R.6H₂O)).

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”.

The term “polymorphs” refers to a crystalline form of a compound (e.g.,compound 1), or a salt, hydrate, or solvate thereof, in a particularcrystal packing arrangement. All polymorphs have the same elementalcomposition. The term “crystalline,” as used herein, refers to a solidstate form which consists of orderly arrangement of structural units.Different crystalline forms of the same compound, or a salt, hydrate, orsolvate thereof, arise from different packing of the molecules in thesolid state, which results in different crystal symmetries and/or unitcell parameter. Different crystalline forms usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Recrystallization solvent, rate of crystallization,storage temperature, and other factors may cause one crystalline form todominate. Various polymorphs of a compound, or a salt, hydrate, orsolvate thereof, can be prepared by crystallization under differentconditions.

As used herein “co-crystals” consist of two or more components that forma unique crystalline structure having unique properties. The onlydifference between a crystalline salt and a co-crystal lies in thetransfer of a proton. The transfer of protons from one component toanother in a crystal is dependent on the environment. For this reason,crystalline salts and co-crystals may be thought of as two ends of aproton transfer spectrum, where the salt has completed the protontransfer at one end and an absence of proton transfer exists forco-crystals at the other end.

As used herein, the term “impurity” refers to extraneous matter includedin a compound (e.g., compound 1), or a pharmaceutically acceptable salt,solvate, hydrate, tautomer, or polymorph thereof. Extraneous matterincludes one or more substances that are different from the compound, orthe pharmaceutically acceptable salt, solvate, hydrate, tautomer, orpolymorph thereof. In certain embodiments, the extraneous matter isundesired extraneous matter. For example, when an anhydrous compound isdesired, the solvent (e.g., water) included in the compound is animpurity. When a crystalline compound is desired, an amorphous form ofthe compound included in the compound is an impurity. When certainpolymorph of a compound is desired, a different polymorph of thecompound included in the compound is an impurity. The term“substantially free of impurities” means that a compound (e.g., compound1), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,or polymorph thereof, contains no significant amount of extraneousmatter (e.g., undesired extraneous matter). What amount of theextraneous matter constitutes a significant amount depends on thesubject matter and is understood in the art. In certain embodiments,about 1 wt %, about 2 wt %, about 3 wt %, about 5 wt %, about 7 wt %, orabout 10 wt % of extraneous matter in a compound, or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, or polymorph thereof, is asignificant amount of extraneous matter.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds(e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female at any stage of development. The animalmay be a transgenic animal or genetically engineered animal. In certainembodiments, the subject is a non-human animal. In certain embodiments,the animal is fish.

The terms “administer,” “administering,” or “administration,” as usedherein, refers to implanting, absorbing, ingesting, injecting, inhaling,or otherwise introducing a compound, or a pharmaceutically acceptablesalt, solvate, hydrate, tautomer, polymorph, or pharmaceuticalcomposition thereof, in or on a subject.

As used herein, the terms “in combination” and “co-administration” canbe used interchangeably to refer to the use of more than one therapy(e.g., one or more prophylactic and/or therapeutic agents). The use ofthe terms does not restrict the order in which therapies (e.g.,prophylactic and/or therapeutic agents) are administered to a subject.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a “pathological condition” (e.g., a disease, disorder, orcondition, or one or more signs or symptoms thereof). In someembodiments, treatment may be administered after one or more signs orsymptoms have developed or have been observed. In other embodiments,treatment may be administered in the absence of signs or symptoms of thedisease or condition. For example, treatment may be administered to asusceptible individual prior to the onset of symptoms. Treatment mayalso be continued after symptoms have resolved, for example, to delay orprevent recurrence.

The terms “prevention,” “prevent,” and “preventing,” as used herein,refer to administering a medicament (e.g., compound 1, or apharmaceutically acceptable salt, solvate, hydrate, tautomer, polymorph,or pharmaceutical composition thereof) beforehand to avert or forestallthe appearance of one or more symptoms of a disease or disorder. Theperson of ordinary skill in the medical art recognizes that the terms“prevention,” “prevent,” and “preventing” are not absolute terms. In themedical art these terms are understood to refer to the prophylacticadministration of a medicament to substantially diminish the likelihoodor seriousness of a condition, or symptom of the condition, and this isthe sense intended in this disclosure.

As used herein, the terms “condition,” “disease,” and “disorder” areused interchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, e.g., treating acondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment. For example,in treating an anxiety disorder, an effective amount of an inventivecompound may provide a therapeutic and/or prophylactic benefit in thetreatment and/or prevention of the anxiety disorder or to delay orminimize one or more symptoms associated with the anxiety disorder.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition (e.g., an anxiety disorder) or to delay or minimize oneor more symptoms associated with the condition. A therapeuticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other therapies, which provides atherapeutic benefit in the treatment of the condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of the condition,or enhances the therapeutic efficacy of another therapeutic agent.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition (e.g., an anxiety disorder),or one or more symptoms associated with the condition or prevent itsrecurrence. A prophylactically effective amount of a compound means anamount of a therapeutic agent, alone or in combination with otheragents, which provides a prophylactic benefit in the prevention of thecondition. The term “prophylactically effective amount” can encompass anamount that improves overall prophylaxis or enhances the prophylacticefficacy of another prophylactic agent.

The term “neurite” refers to any projection from the cell body of aneuron. This projection can be either an axon or a dendrite. Neuritesare often packed with microtubule bundles, the growth of which isstimulated by Nerve Growth Factor (NGF), as well as tau proteins, MAP1,and MAP2. The neural cell adhesion molecule N-CAM simultaneouslycombines with another N-CAM and a fibroblast growth factor receptor tostimulate the tyrosine kinase activity of that receptor to induce thegrowth of neurites.

A disease“responsive to neurite outgrowth” is a disease, disorder, orcondition which may be ameliorated by enhancement of neurite outgrowth.Diseases responsive to neurite outgrowth include neurodegenerativediseases (e.g., multiple sclerosis and a Parkinsonian related disorder)and diseases that involve neural damage that include wound healing,spinal cord injury, and peripheral nerve disorders.

The present application refers to various issued patent, publishedpatent applications, journal articles, and other publications, all ofwhich are incorporated herein by reference.

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the Figures, the Examples, andthe Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of Form A(middle curve).

FIG. 2 depicts Fourier-Transform Raman (FT-Raman) spectrum of Form A(top curve).

FIG. 3 depicts an XRPD pattern of Form C.

FIG. 4 depicts an FT-Raman spectrum of Form C.

FIG. 5 depicts a Differential Scanning Calorimetry (DSC) thermogram ofForm C.

FIG. 6 depicts a Dynamic Vapor Sorption (DVS) isotherm of Form C.

FIG. 7 depicts a Thermogravimetric Fourier-Transform Infrared (TG-FTIR)thermogram of Form C.

FIG. 8 depicts a microscopic image with crossed polarizers of Form C.

FIG. 9 depicts an XRPD pattern of Form D.

FIG. 10 depicts an FT-Raman spectrum of Form D.

FIG. 11 depicts a DSC thermogram of Form D.

FIG. 12 depicts a TG-FTIR thermogram of Form D.

FIG. 13 depicts an XRPD pattern of Form E.

FIG. 14 depicts an FT-Raman spectrum of Form E.

FIG. 15 depicts a TG-FTIR thermogram of Form E.

FIG. 16 depicts an XRPD pattern of Form F.

FIG. 17 depicts an FT-Raman spectrum of Form F.

FIG. 18 depicts a TG-FTIR thermogram of Form F.

FIG. 19 depicts an XRPD pattern of Form G.

FIG. 20 depicts an FT-Raman spectrum of Form G.

FIG. 21 depicts a TG-FTIR thermogram of Form G.

FIG. 22 depicts an XRPD pattern of Form H.

FIG. 23 depicts an FT-Raman spectrum of Form H.

FIG. 24 depicts a TG-FTIR thermogram of Form H.

FIG. 25 depicts an XRPD pattern of Form I.

FIG. 26 depicts an FT-Raman spectrum of Form I.

FIG. 27 depicts a TG-FTIR thermogram of Form I.

FIG. 28 depicts an XRPD pattern of Form J.

FIG. 29 depicts an FT-Raman spectrum of Form J.

FIG. 30 depicts a TG-FTIR thermogram of Form J.

FIG. 31 depicts an XRPD pattern of Form K.

FIG. 32 depicts an FT-Raman spectrum of Form K.

FIG. 33 depicts a TG-FTIR thermogram of Form K.

FIG. 34 depicts an XRPD pattern of Form L.

FIG. 35 depicts an FT-Raman spectrum of Form L.

FIG. 36 depicts a TG-FTIR thermogram of Form L.

FIG. 37 depicts an XRPD pattern of Form M.

FIG. 38 depicts an FT-Raman spectrum of Form M.

FIG. 39 depicts a TG-FTIR thermogram of Form M.

FIG. 40 depicts an XRPD pattern of Form FUM-P3.

FIG. 41 depicts an FT-Raman spectrum of Form FUM-P3.

FIG. 42 depicts a DSC thermogram of Form FUM-P3.

FIG. 43 depicts a DVS isotherm of Form FUM-P3.

FIG. 44 depicts a TG-FTIR thermogram of Form FUM-P3.

FIG. 45 depicts an XRPD pattern of Form FUM-P4.

FIG. 46 depicts an FT-Raman spectrum of Form FUM-P4.

FIG. 47 depicts a TG-FTIR thermogram of Form FUM-P4.

FIG. 48 depicts an XRPD pattern of Form MLA-P3.

FIG. 49 depicts an FT-Raman spectrum of Form MLA-P3.

FIG. 50 depicts a DSC thermogram of Form MLA-P3.

FIG. 51 depicts an XRPD pattern of Form MLA-P4.

FIG. 52 depicts an FT-Raman spectrum of Form MLA-P4

FIG. 53 depicts a DSC thermogram of Form MLA-P4.

FIG. 54 depicts a DVS isotherm of Form MLA-P4.

FIG. 55 depicts a TG-FTIR thermogram of Form MLA-P4.

FIG. 56 depicts an XRPD pattern of Form SUC-P3.

FIG. 57 depicts an FT-Raman spectrum of Form SUC-P3

FIG. 58 depicts a DSC thermogram of Form SUC-P3.

FIG. 59 depicts a TG-FTIR thermogram of Form SUC-P3.

FIG. 60 depicts an XRPD pattern of Form SUC-P4.

FIG. 61 depicts an FT-Raman spectrum of Form SUC-P4.

FIG. 62 depicts a DSC thermogram of Form SUC-P4.

FIG. 63 depicts a DVS isotherm of Form SUC-P4.

FIG. 64 depicts a TG-FTIR thermogram of Form SUC-P4.

FIG. 65 depicts an XRPD pattern of Form MLE-P4.

FIG. 66 depicts an FT-Raman spectrum of Form MLE-P4

FIG. 67 depicts a DSC thermogram of Form MLE-P4.

FIG. 68 depicts a TG-FTIR thermogram of Form MLE-P4.

FIG. 69 depicts a Proton Nuclear Magnetic Resonance (¹H-NMR) spectrum ofForm C.

FIG. 70 depicts a ¹H-NMR spectrum of Form D.

FIG. 71 depicts a ¹H-NMR spectrum of Form H.

FIG. 72 depicts a ¹H-NMR spectrum of Form 1.

FIG. 73 depicts a ¹H-NMR spectrum of Form J.

FIG. 74 depicts a ¹H-NMR spectrum of Form K.

FIG. 75 depicts a ¹H-NMR spectrum of Form L.

FIG. 76 depicts a ¹H-NMR spectrum of Form M.

FIG. 77 depicts a ¹H-NMR spectrum of Form FUM-P3.

FIG. 78 depicts a ¹H-NMR spectrum of Form FUM-P4.

FIG. 79 depicts a ¹H-NMR spectrum of Form MLA-P3.

FIG. 80 depicts a ¹H-NMR spectrum of Form MLA-P4.

FIG. 81 depicts a ¹H-NMR spectrum of Form SUC-P3.

FIG. 82 depicts a ¹H-NMR spectrum of Form SUC-P4.

FIG. 83 depicts a ¹H-NMR spectrum of Form MLE-P4.

FIG. 84 depicts a XRPD pattern of Form MLE-P6.

FIGS. 85A-85B depict an infrared (IR) spectrum of Form C.

FIG. 86 depict another IR spectrum of Form C.

FIG. 87 depicts an XRPD pattern of Form SUC-P5.

FIG. 88 depicts a DSC thermogram of Form SUC-P5.

FIG. 89 depicts a 1H-NMR spectrum of Form SUC-P5.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

Compound 1(1-ethyl-6-(indan-2-ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4-one)has been reported to elicit an anxiolytic effect. Compound 1 has shownsignificant potential for the treatment of a variety of disorders of thecentral nervous system (CNS), such as anxiety disorders. See, e.g., U.S.Pat. No. 8,293,737.

In some embodiments, it would be desirable to provide a crystallinepolymorph of compound 1 that, as compared to the amorphous compound 1,imparts improved physical characteristics such as improved aqueoussolubility, stability, and/or ease of formulation. Accordingly, providedherein are various crystalline forms of compound 1.

In some embodiments, a provided crystalline form of compound 1 issubstantially anhydrous. In some embodiments, a provided crystallineform of compound 1 is a hydrate. In some embodiments, a providedcrystalline form of compound 1 is a hemihydrate. In some embodiments, aprovided crystalline form of compound 1 is a non-stoichiometric hydrate.In some embodiments, a provided crystalline form of compound 1 is asolvate. In some embodiments, a provided crystalline form of compound 1is a hemisolvate. In some embodiments, a provided crystalline form ofcompound 1 is a non-stoichiometric solvate.

In some embodiments, it would be desirable to provide a salt form ofcompound 1 that, as compared to compound 1, imparts characteristics suchas improved aqueous solubility, stability, and ease of formulation.Accordingly, the present disclosure also provides salts of compound 1.In certain embodiments, a provided salt of compound 1 is an acidaddition salt. Also provided herein are crystalline polymorphs ofcertain acid addition salts of compound 1. Also provided herein areamorphous forms of compound 1 (such as amorphous Form A) and amorphousforms of certain acid addition salts of compound 1.

In certain embodiments, the present disclosure provides a fumarate saltof compound 1. In certain embodiments, the present disclosure providesan L-malate salt of compound 1. In certain embodiments, the presentdisclosure provides an D-malate salt of compound 1. In certainembodiments, the present disclosure provides a succinate salt ofcompound 1. In certain embodiments, the present disclosure provides amaleate salt of compound 1. In certain embodiments, the presentdisclosure provides a thiocyanate salt of compound 1. In certainembodiments, the present disclosure provides an oxalate salt ofcompound 1. In certain embodiments, the present disclosure provides abenzoate salt of compound 1. In certain embodiments, the presentdisclosure provides a 2-oxoglutarate salt of compound 1. In certainembodiments, the present disclosure provides a tartrate salt of compound1.

It will be appreciated by one of ordinary skill in the art that the acid(e.g., fumaric acid, L-malic acid, D-malic acid, succinic acid, maleicacid, thiocyanic acid, oxalic acid, benzoic acid, or 2-oxoglutaric acid)and compound 1 are ionically bonded to form an acid addition salt. Itwill also be appreciated that various stoichiometries of compound 1 to aprovided acid are possible. It is contemplated that salts of compound 1can exist in a variety of physical forms. For example, a salt ofcompound 1 (e.g., a fumarate, L-malate, D-malate, succinate, maleate,thiocyanate, oxalate, benzoate, 2-oxoglutarate, or tartrate salt) can bein solution, suspension, or in solid form. In certain embodiments, asalt of compound 1 (e.g., a fumarate, L-malate, D-malate, succinate,maleate, thiocyanate, oxalate, benzoate, 2-oxoglutarate, or tartratesalt) is in solid form. When a salt of compound 1 (e.g., a fumarate,L-malate, D-malate, succinate, maleate, thiocyanate, oxalate, benzoate,2-oxoglutarate, or tartrate salt) is in solid form, said compound may beamorphous, crystalline, or a mixture thereof. A solid form of a salt ofcompound 1 (e.g., a fumarate, L-malate, D-malate, succinate, maleate,thiocyanate, oxalate, benzoate, 2-oxoglutarate, or tartrate salt) mayexist in neat (non-solvated) form, or as a solvate (e.g., a hydrate).Exemplary solid forms are described in more detail below.

In certain embodiments, the present invention provides compound 1, or afumarate, L-malate, D-malate, succinate, maleate, thiocyanate, oxalate,benzoate, 2-oxoglutarate, or tartrate salt thereof, substantially freeof impurities. Such extraneous matter may include excess salt formingacid, excess compound 1, residual solvents, or any other impurities thatmay result from the preparation, and/or isolation, of compound 1, or afumarate, L-malate, D-malate, succinate, maleate, thiocyanate, oxalate,benzoate, 2-oxoglutarate, or tartrate salt thereof. In certainembodiments, at least about 95% by weight of compound 1 is present. Incertain embodiments, at least about 95% by weight of a fumarate,L-malate, D-malate, succinate, maleate, thiocyanate, oxalate, benzoate,2-oxoglutarate, or tartrate salt of compound 1 is present. In certainembodiments, at least about 99% by weight of compound 1 is present. Incertain embodiments, at least about 99% by weight of a fumarate,L-malate, D-malate, succinate, maleate, thiocyanate, oxalate, benzoate,2-oxoglutarate, or tartrate salt of compound 1 is present.

In certain embodiments, compound 1 is present in an amount of at leastabout 97, 97.5, 98, 98.5, 99, 99.5, 99.8 weight percent where thepercentages are based on the total weight of the composition. In certainembodiments, a fumarate, L-malate, D-malate, succinate, maleate,thiocyanate, oxalate, benzoate, 2-oxoglutarate, or tartrate salt ofcompound 1 is present in an amount of at least about 97, 97.5, 98, 98.5,99, 99.5, 99.8 weight percent where the percentages are based on thetotal weight of the composition. In certain embodiments, compound 1contains no more than about 3.0 area percent HPLC of total organicimpurities and, in certain embodiments, no more than about 1.5 areapercent HPLC total organic impurities relative to the total area of theHPLC chromatogram. In certain embodiments, a fumarate, L-malate,D-malate, succinate, maleate, thiocyanate, oxalate, benzoate,2-oxoglutarate, or tartrate salt of compound 1 contains no more thanabout 3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 1 contains no more than about 1.0 area percentHPLC of any single impurity, and, in certain embodiments, no more thanabout 0.6 area percent HPLC of any single impurity, and, in certainembodiments, no more than about 0.5 area percent HPLC of any singleimpurity, relative to the total area of the HPLC chromatogram. In otherembodiments, a fumarate, L-malate, D-malate, succinate, maleate,thiocyanate, oxalate, benzoate, 2-oxoglutarate, or tartrate salt ofcompound 1 contains no more than about 1.0 area percent HPLC of anysingle impurity, and, in certain embodiments, no more than about 0.6area percent HPLC of any single impurity, and, in certain embodiments,no more than about 0.5 area percent HPLC of any single impurity,relative to the total area of the HPLC chromatogram.

The structure depicted for compound 1, or a salt thereof, are also meantto include all tautomeric forms of compound 1 or salts thereof.Additionally, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the structure of compound1, or a fumarate, L-malate, D-malate, succinate, maleate, thiocyanate,oxalate, benzoate, 2-oxoglutarate, or tartrate salt thereof, except forthe replacement of hydrogen by deuterium or tritium, or the replacementof a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of thepresent invention.

Solid Forms

Compound 1, or a fumarate, L-malate, D-malate, succinate, maleate,thiocyanate, oxalate, benzoate, 2-oxoglutarate, or tartrate saltthereof, has been found to exist in a variety of solid forms. Such formsinclude polymorphs, solvates, hydrates, and amorphous forms. All suchforms are contemplated herein. In certain embodiments, the presentinvention provides compound 1 as a composition of one or more solidforms selected from polymorphs, solvates, hydrates, and amorphous formsof compound 1. In certain embodiments, the present invention provides afumarate salt of compound 1 as a composition of one or more solid formsselected from polymorphs, solvates, hydrates, and amorphous forms of afumarate salt of compound 1. In certain embodiments, the presentinvention provides an L-malate salt of compound 1 as a composition ofone or more solid forms selected from polymorphs, solvates, hydrates,and amorphous forms of an L-malate salt of compound 1. In certainembodiments, the present invention provides an D-malate salt of compound1 as a composition of one or more solid forms selected from polymorphs,solvates, hydrates, and amorphous forms of a D-malate salt ofcompound 1. In certain embodiments, the present invention provides asuccinate salt of compound 1 as a composition of one or more solid formsselected from polymorphs, solvates, hydrates, and amorphous forms of asuccinate salt of compound 1. In certain embodiments, the presentinvention provides a maleate salt of compound 1 as a composition of oneor more solid forms selected from polymorphs, solvates, hydrates, andamorphous forms of a maleate salt of compound 1. In certain embodiments,the present invention provides a thiocyanate salt of compound 1 as acomposition of one or more solid forms selected from polymorphs,solvates, hydrates, and amorphous forms of a thiocyanate salt ofcompound 1. In certain embodiments, the present invention provides anoxalate salt of compound 1 as a composition of one or more solid formsselected from polymorphs, solvates, hydrates, and amorphous forms of anoxalate salt of compound 1. In certain embodiments, the presentinvention provides a benzoate salt of compound 1 as a composition of oneor more solid forms selected from polymorphs, solvates, hydrates, andamorphous forms of a benzoate salt of compound 1. In certainembodiments, the present invention provides a 2-oxoglutarate salt ofcompound 1 as a composition of one or more solid forms selected frompolymorphs, solvates, hydrates, and amorphous forms of a 2-oxoglutaratesalt of compound 1. In certain embodiments, the present inventionprovides a tartrate salt of compound 1 as a composition of one or moresolid forms selected from polymorphs, solvates, hydrates, and amorphousforms of a tartrate salt of compound 1.

Different solid forms of a compound typically differ in their physicaland chemical properties based on the arrangement of the molecules in thesolid form (e.g., the arrangement of the molecule in the crystallattice). A given substance may give rise to a variety of solid forms,in particular a variety of crystalline forms, wherein each form hasdifferent and distinct physical and chemical properties, such assolubility profiles, thermodynamic and chemical stabilities, meltingpoints, Raman spectra, and/or x-ray diffraction peaks.

Different solid forms of a compound can be typically distinguished byX-ray diffraction, in particular X-ray powder diffraction (XRPD) and byother methods, such as, for example, differential scanning calorimetry(DSC), infrared spectroscopy, and/or Raman spectroscopy.

Form A

Compound 1 may be present in an amorphous solid form. Amorphous solidsare well known to those of ordinary skill in the art and are typicallyprepared by such methods as lyophilization, melting, and precipitationfrom supercritical fluid, among others. In some embodiments, the presentinvention provides an amorphous form of compound 1 referred to herein asamorphous Form A (Form A). In certain embodiments, Form A issubstantially free of impurities. In certain embodiments, Form A is 99%free of impurities by weight. In certain embodiments, Form A is 97% freeof impurities by weight. In certain embodiments, Form A is 95% free ofimpurities by weight. In certain embodiments, Form A is substantiallyfree of crystalline compound 1. In certain embodiments, Form A issubstantially free of a salt of compound 1. In certain embodiments, FormA is substantially free of a solvate of compound 1. In certainembodiments, amorphous Form A is substantially anhydrous. In certainembodiments, Form A comprises at least about 95% by weight of amorphouscompound 1. In certain embodiments, Form A comprises at least about 97%by weight of amorphous compound 1. In certain embodiments, Form Acomprises at least about 99% by weight of amorphous compound 1.

Form A can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In certain embodiments, Form A ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 1. In certain embodiments, Form A ischaracterized by a Raman spectrum substantially similar to the onedepicted in FIG. 2.

In certain embodiments, Form A has an observed melting point of about148-156° C.

In certain embodiments, Form A is obtained from quench cooling of melt.In certain embodiments, Form A is obtained from fast evaporation from ahalogenated hydrocarbon solvent (e.g., dichloromethane (DCM)).

Form C

Compound 1 may also be present in a solid crystalline form. In certainembodiments, compound 1 is present as a crystalline solid substantiallyfree of amorphous compound 1. In certain embodiments, at least 95% byweight of crystalline compound 1 is present. In certain embodiments, atleast 99% by weight of crystalline compound 1 is present.

In certain embodiments, compound 1 is a neat crystal form and thus doesnot have any water or solvent incorporated into the crystal structure.It has been found that compound 1 can exist in at least two distinctneat (i.e., anhydrous) crystalline forms, i.e., Form C and Form D. Insome embodiments, the present invention provides a polymorphic form ofcompound 1 referred to herein as Form C.

In certain embodiments, Form C is substantially free of impurities. Incertain embodiments, Form C is 99% free of impurities by weight. Incertain embodiments, Form C is 97% free of impurities by weight. Incertain embodiments, Form C is 95% free of impurities by weight. Incertain embodiments, Form C is substantially free of amorphouscompound 1. In certain embodiments, Form C is substantially free ofother crystalline forms of compound 1. In certain embodiments, Form C issubstantially free of a salt of compound 1. Form C is not a solvate orhydrate of compound 1.

Form C can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form C of compound 1 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 3. In some embodiments, Form C ofcompound 1 is characterized in that it has one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 2. In someembodiments, Form C of compound 1 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, at least nine, at least ten, at leasteleven, at least twelve, at least thirteen, at least fourteen, at leastfifteen, or at least sixteen peaks in its X-ray powder diffractionpattern selected from those in Table 2. In some embodiments, Form C ofcompound 1 is characterized in that it has one or more peaks in itsX-ray powder diffraction pattern selected from the strong and verystrong peaks in Table 2.

TABLE 2 X-ray powder diffraction pattern of Form C. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 4.05 21.8 w 15 5.8915.0 s 37 8.33 10.6 s 41 9.33 9.5 s 40 11.82 7.5 m 26 12.53 7.1 w 1315.09 5.86 vs 100 17.29 5.12 s 49 17.78 4.99 w 14 18.75 4.73 m 27 20.974.23 w 15 21.44 4.14 w 14 22.04 4.03 w 14 4.05 21.8 w 15 22.66 3.92 m 1726.69 3.34 w 12 27.11 3.29 w 14

The terms used in the tables with XRPD data herein have the followingmeanings: The term “vs” stands for “very strong.” The term “s” standsfor “strong.” The term “m” stands for “medium.” The term “w” stands for“weak.” The term “vw” stands for “very weak.”

In some embodiments, Form C of compound 1 is characterized by one ormore peaks in its X-ray powder diffraction pattern selected from thosein Table 3. In some embodiments, Form C of compound 1 is characterizedby at least one, at least two, at least three, at least four, at leastfive, or at least six peaks in its X-ray powder diffraction patternselected from those in Table 3.

TABLE 3 Select characteristic peaks of the X-ray powder diffractionpattern of Form C. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 8.33 10.6 s 41 9.33 9.5 s 40 11.82 7.5 m 26 15.09 5.86 vs100 17.29 5.12 s 49 18.75 4.73 m 27

In some embodiments, Form C of compound 1 is characterized by a Ramanspectrum substantially similar to the one depicted in FIG. 4. In someembodiments, Form C of compound 1 is characterized by one or more peaksin its Raman spectrum selected from those in Table 4. In someembodiments, Form C of compound 1 is characterized by having a Ramanspectrum with characteristic peaks at about those in Table 4.

TABLE 4 Raman spectrum of Form C. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3326 0.236 6.6 3080 0.816 22.8 3068 0.675 18.93041 1.734 48.5 3017 0.812 22.7 3000 0.810 22.7 2975 2.952 82.6 29291.466 41.0 2876 1.069 29.9 2863 1.127 31.6 2853 1.119 31.3 1627 2.31664.8 1611 3.220 90.1 1602 3.572 100.0 1501 1.513 42.4 1476 0.435 12.21459 1.170 32.8 1448 1.046 29.3 1427 1.357 38.0 1396 1.153 32.3 13760.431 12.1 1346 1.383 38.7 1301 0.548 15.3 1281 0.569 15.9 1247 0.48413.5 1228 0.438 12.3 1212 0.670 18.8 1198 0.325 9.1 1158 0.241 6.7 11240.301 8.4 1089 0.355 9.9 1062 0.531 14.9 1035 0.753 21.1 1028 1.016 28.41009 0.714 20.0 994 0.639 17.9 941 0.307 8.6 922 0.210 5.9 865 0.64218.0 855 0.732 20.5 822 0.479 13.4 790 1.165 32.6 739 1.061 29.7 7130.519 14.5 682 0.412 11.5 577 0.442 12.4 539 0.330 9.2 520 0.261 7.3 4930.321 9.0 479 0.335 9.4 466 0.386 10.8 438 0.320 9.0 418 0.405 11.3 3950.494 13.8 356 0.296 8.3 325 0.624 17.5 306 0.254 7.1 258 0.518 14.5 2420.590 16.5 214 0.667 18.7 191 0.865 24.2

In some embodiments, Form C of compound 1 is characterized by one ormore peaks in its Raman spectrum selected from those in Table 5. In someembodiments, Form C of compound 1 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, or at least nine peaks in its Ramanspectrum selected from those in Table 5.

TABLE 5 Select characteristic peaks of the Raman spectrum of Form CWavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1627 2.31664.8 1611 3.220 90.1 1602 3.572 100.0 1501 1.513 42.4 1459 1.170 32.81427 1.357 38.0 1396 1.153 32.3 1346 1.383 38.7 790 1.165 32.6

In some embodiments, Form C has a DSC thermogram substantially similarto the one depicted in FIG. 5. In some embodiments, Form C ischaracterized in that it has a DSC thermogram with an endotherm having apeak temperature (T_(max)) of about 212° C. In some embodiments, Form Cis characterized in that it has a DSC thermogram with a ΔH of about 99J/g.

In some embodiments, Form C has a DVS isotherm substantially similar tothe one depicted in FIG. 6.

In some embodiments, Form C has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 7.

In some embodiments, Form C of compound 1 is characterized by an IRspectrum substantially similar to the one depicted in FIGS. 85A and 85B.In some embodiments, Form C of compound 1 is characterized by an IRspectrum substantially similar to the one depicted in FIG. 86. In someembodiments, Form C of compound 1 is characterized by one or more peaksin its IR spectrum selected from those in Table 85.

TABLE 85 IR spectrum No. cm−1 % T No. cm−1 % T No. cm−1 % T 1 3324.6820.8781 2 3066.26 71.334 3 3023.84 67.3925 4 2996.84 75.1349 5 2968.8742.8261 6 2915.84 56.8473 7 2878.24 54.994 8 2859.92 48.5373 9 1832.0485.8173 10 1603.52 0.306526 11 1499.38 2.08717 12 1482.99 18.9158 131461.78 11.4636 14 1445.39 11.5874 15 1394.28 41.3824 16 1373.07 28.1517 1345.11 29.8025 18 1318.11 31.4519 19 1270.86 25.2928 20 1240.977.18615 21 1157.08 84.3949 22 1131.05 53.4389 23 1113.69 13.9215 241087.66 62.5416 25 1070.3 59.1501 26 1031.73 62.5165 27 1015.34 70.77828 993.16 39.8618 29 940.128 71.7559 30 916.022 55.1066 31 887.09554.0377 32 853.347 66.128 33 806.099 48.9103 34 785.85 58.69 35 737.63924.5861 36 682.677 66.7085 37 635.43 62.8494 38 576.612 34.7937 39554.434 63.3669 40 519.722 65.9416 41 485.009 74.4132 42 464.761 67.977243 417.513 78.5559 44 408.835 77.593

In certain embodiments, Form C is fine hairs or needles. In certainembodiments, Form C has a microscopic image with crossed polarizerssubstantially similar to the one depicted in FIG. 8.

In certain embodiments, Form C has an observed melting point from about204° C. to about 211° C. In some embodiments, Form C has an observedaqueous solubility of about 0.04 mg/mL at about 25° C. In someembodiments, Form C is obtained from ethanol/water. In some embodiments,Form C is obtained from ethanol/water (1:1 v/v). In some embodiments,Form C is stable for at least about 1 month, at least about 2 months, atleast about 4 months, at least about 6 months, at least about 12 months,at least about 18 months, at least about 24 months, or at least about 3years at about 25° C. and about 60% relative humidity. In someembodiments, Form C has substantially the same XRPD pattern post storagefor at least about 1 month, at least about 2 months, at least about 4months, at least about 6 months, at least about 12 months, at leastabout 18 months, at least about 24 months, or at least about 3 years atabout 25° C. and about 60% relative humidity. In some embodiments, FormC has substantially the same IR spectrum post storage for at least about1 month, at least about 2 months, at least about 4 months, at leastabout 6 months, at least about 12 months, at least about 18 months, atleast about 24 months, or at least about 3 years at about 25° C. andabout 60% relative humidity.

In some embodiments, Form C is stable for at least about 1 month, atleast about 2 months, at least about 4 months, at least about 6 months,at least about 8 months, at least about 10 months, at least about 12months, at least about 18 months, or at least about 24 months at about40° C. and about 75% relative humidity. In some embodiments, Form C hassubstantially the same XRPD pattern post storage for at least about 1month, at least about 2 months, at least about 4 months, at least about6 months, at least about 8 months, at least about 10 months, at leastabout 12 months, at least about 18 months, or at least about 24 monthsat about 40° C. and about 75% relative humidity. In some embodiments,Form C has substantially the same IR spectrum post storage for at leastabout 1 month, at least about 2 months, at least about 4 months, atleast about 6 months, at least about 8 months, at least about 10 months,at least about 12 months, at least about 18 months, or at least about 24months at about 40° C. and about 75% relative humidity.

Form D

In some embodiments, the present invention provides a polymorphic formof compound 1 referred to herein as crystalline Form D (Form D). Incertain embodiments, Form D is substantially anhydrous. In certainembodiments, Form D is 99% anhydrous by weight. In certain embodiments,Form D is 97% anhydrous by weight. In certain embodiments, Form D is 95%anhydrous by weight. In certain embodiments, Form D is substantiallyfree of impurities. In certain embodiments, Form D is 99% free ofimpurities by weight. In certain embodiments, Form D is 97% free ofimpurities by weight. In certain embodiments, Form D is 95% free ofimpurities by weight. In certain embodiments, crystalline Form D issubstantially free of amorphous compound 1. In certain embodiments,crystalline Form D is substantially free of other crystalline forms ofcompound 1. In certain embodiments, crystalline Form D is substantiallyfree of a salt of compound 1. In certain embodiments, crystalline Form Dis substantially free of a solvate of compound 1.

Form D can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, crystalline Form D ofcompound 1 is characterized by an X-ray powder diffraction patternsubstantially similar to the one depicted in FIG. 9. In someembodiments, crystalline Form D of compound 1 is characterized in thatit has one or more peaks in its X-ray powder diffraction patternselected from those in Table 6. In some embodiments, crystalline Form Dof compound 1 is characterized by at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, at least nine, at least ten, at least eleven, at leasttwelve, at least thirteen, at least fourteen, at least fifteen, at leastsixteen, at least seventeen, at least eighteen, at least nineteen, atleast twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, at least twenty-seven, or at least twenty-eight peaks in itsX-ray powder diffraction pattern selected from those in Table 6. In someembodiments, Form D of compound 1 is characterized in that it has one ormore peaks in its X-ray powder diffraction pattern selected from thestrong and very strong peaks in Table 6.

TABLE 6 X-ray powder diffraction pattern of Form D. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 4.10 21.5 m 29 4.6918.8 m 25 7.54 11.7 s 56 8.22 10.7 s 46 8.43 10.5 s 38 9.31 9.5 s 3611.20 7.9 m 18 11.94 7.4 s 38 12.90 6.9 s 38 14.25 6.2 vs 72 14.80 5.98vs 100 16.15 5.48 m 25 16.54 5.36 m 24 17.34 5.11 s 49 18.71 4.74 s 4419.43 4.57 s 34 20.08 4.42 s 36 20.82 4.26 s 32 21.75 4.08 s 62 23.313.81 m 26 23.99 3.71 s 32 24.39 3.65 s 45 24.91 3.57 s 35 25.54 3.49 m25 26.52 3.36 s 31 27.08 3.29 m 27 32.72 2.73 m 20 33.08 2.71 m 17

In some embodiments, crystalline Form D of compound 1 is characterizedby one or more peaks in its X-ray powder diffraction pattern selectedfrom those in Table 7. In some embodiments, crystalline Form D ofcompound 1 is characterized by at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, or atleast eight in its X-ray powder diffraction pattern selected from thosein Table 7.

TABLE 7 Select characteristic peaks of the X-ray powder diffractionpattern of Form D. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 7.54 11.7 s 56 8.22 10.7 s 46 14.25 6.2 vs 72 14.80 5.98 vs100 17.34 5.11 s 49 18.71 4.74 s 44 21.75 4.08 s 62 24.39 3.65 s 45

In some embodiments, crystalline Form D of compound 1 is characterizedby a Raman spectrum substantially similar to the one depicted in FIG.10. In some embodiments, crystalline Form D of compound 1 ischaracterized by one or more peaks in its Raman spectrum selected fromthose in Table 8. In some embodiments, crystalline Form D of compound 1is characterized by having a Raman spectrum with characteristic peaks atabout those in Table 8.

TABLE 8 Raman spectrum of Form D. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3068 0.141 16.7 3040 0.241 28.6 3004 0.163 19.42977 0.410 48.7 2952 0.241 28.6 2929 0.255 30.3 2872 0.223 26.5 16280.453 53.8 1605 0.842 100.0 1502 0.378 44.9 1448 0.319 37.9 1427 0.35041.6 1394 0.284 33.7 1347 0.338 40.1 1302 0.171 20.3 1281 0.172 20.41245 0.157 18.6 1210 0.187 22.2 1123 0.122 14.5 1089 0.122 14.5 10620.168 20.0 1035 0.210 24.9 1027 0.304 36.1 1009 0.213 25.3 996 0.20424.2 942 0.113 13.4 919 0.106 12.6 855 0.213 25.3 821 0.148 17.6 8070.146 17.3 792 0.299 35.5 740 0.312 37.1 714 0.194 23.0 680 0.176 20.9578 0.169 20.1 540 0.164 19.5 493 0.179 21.3 466 0.180 21.4 438 0.18321.7 418 0.190 22.6 395 0.210 24.9 358 0.168 20.0 326 0.233 27.7 2610.235 27.9 211 0.259 30.8 186 0.303 36.0

In some embodiments, crystalline Form D of compound 1 is characterizedby one or more peaks in its Raman spectrum selected from those in Table9. In some embodiments, crystalline Form D of compound 1 ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, or at least ten peaks in its Raman spectrum selected fromthose in Table 9.

TABLE 9 Select characteristic peaks of the Raman spectrum of Form D.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1628 0.45353.8 1605 0.842 100.0 1502 0.378 44.9 1448 0.319 37.9 1427 0.350 41.61394 0.284 33.7 1347 0.338 40.1 1027 0.304 36.1 792 0.299 35.5 740 0.31237.1

In some embodiments, Form D has a DSC thermogram substantially similarto the one depicted in FIG. 11. In some embodiments, Form D ischaracterized in that it has a DSC thermogram with endotherm peaktemperatures (T_(max)) of about 162° C., about 176° C., and about 205°C. In some embodiments, Form D is characterized in that it has a DSCthermogram with ΔH values of about 27.8 J/g, about 24.3 J/g, and about13.7 J/g.

In some embodiments, Form D is characterized by a TG-FTIR thermogramsubstantially similar to the one depicted in FIG. 12.

In some embodiments, Form D is obtained from drying Form E under vacuum.In some embodiments, Form D is obtained from drying Form E at a pressureof lower than about 5 mbar for about 12 hours, about 1 day, about 2days, or about 3 days. In some embodiments, Form D is stable for atleast about 1 month, at least about 2 months, at least about 4 months,at least about 6 months, at least about 12 months, at least about 18months, at least about 2 years, or at least about 3 years at about 25°C. and about 60% relative humidity.

In certain embodiments, compound 1 is a solvated crystal form and thushas solvent (e.g., MeOH, EtOH, 2-PrOH, 1-BuOH, THF, EtOAc, dioxane,pyridine, or DMSO) incorporated into the crystal structure. It has beenfound that compound 1 can exist in multiple solvate crystal forms, orpolymorphs. In some embodiments, the present invention provides apolymorphic form of compound 1 referred to herein as crystalline Form E.

In certain embodiments, Form E is substantially free of impurities. Incertain embodiments, Form E is 99% free of impurities by weight. Incertain embodiments, Form E is 97% free of impurities by weight. Incertain embodiments, Form E is 95% free of impurities by weight. Incertain embodiments, Form E is substantially free of amorphouscompound 1. In certain embodiments, Form E is substantially free ofother crystalline forms of compound 1. In certain embodiments, Form E issubstantially free of a salt of compound 1.

Form E can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form E is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 13. In some embodiments, Form E is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 10. In some embodiments, Form E ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, at least twenty,at least twenty-one, at least twenty-two, at least twenty-three, atleast twenty-four, at least twenty-five, at least twenty-six, at leasttwenty-seven peaks in its X-ray powder diffraction pattern selected fromthose in Table 10. In some embodiments, Form E of compound 1 ischaracterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 10.

TABLE 10 X-ray powder diffraction pattern of Form E. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 4.02 22.0 s 32 4.4319.9 w 14 7.26 12.2 s 55 7.88 11.2 vs 100 8.75 10.1 m 19 11.14 7.9 s 3611.36 7.8 s 32 12.02 7.4 s 36 13.38 6.6 s 31 14.29 6.2 s 48 15.69 5.64 s37 16.33 5.42 m 27 17.82 4.97 s 42 18.23 4.86 s 40 18.63 4.76 m 28 19.764.49 s 35 20.11 4.41 s 42 20.52 4.32 m 30 20.97 4.23 s 30 21.34 4.16 s32 22.25 3.99 s 46 22.66 3.92 s 37 23.54 3.78 m 29 24.01 3.70 m 27 25.053.55 m 30 27.39 3.25 m 26 29.25 3.05 m 17

In some embodiments, Form E is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 11. Insome embodiments, Form E is characterized by at least one, at least two,at least three, at least four, at least five, or at least seven peaks inits X-ray powder diffraction pattern selected from those in Table 11.

TABLE 11 Select characteristic peaks of the X-ray powder diffractionpattern of Form E. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 7.26 12.2 s 55 7.88 11.2 vs 100 14.29 6.2 s 48 17.82 4.97 s42 18.23 4.86 s 40 20.11 4.41 s 42 22.25 3.99 s 46

In some embodiments, Form E is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 14. In someembodiments, Form E is characterized by one or more peaks in its Ramanspectrum selected from those in Table 12. In some embodiments, Form E ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 12.

TABLE 12 Raman spectrum of Form E. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3346 0.116 5.7 3071 0.469 23.1 3043 0.668 33.02985 0.654 32.3 2966 0.913 45.1 2931 1.355 66.9 2910 0.848 41.9 28780.517 25.5 1606 1.621 80.0 1503 0.780 38.5 1448 0.661 32.6 1429 0.74937.0 1391 0.676 33.4 1352 0.605 29.9 1343 0.578 28.5 1324 0.391 19.31301 0.287 14.2 1273 0.485 23.9 1244 0.254 12.5 1220 0.294 14.5 12070.383 18.9 1153 0.243 12.0 1125 0.216 10.7 1088 0.265 13.1 1062 0.29814.7 1035 0.376 18.6 1026 0.795 39.2 999 0.495 24.4 928 0.181 8.9 8520.318 15.7 806 0.723 35.7 789 0.826 40.8 742 0.362 17.9 720 0.544 26.9680 0.354 17.5 577 0.250 12.3 549 0.323 15.9 520 0.238 11.7 480 0.34216.9 466 0.267 13.2 443 0.294 14.5 411 0.296 14.6 395 0.280 13.8 3550.238 11.7 331 0.312 15.4 255 0.437 21.6 198 0.613 30.3 157 0.609 30.1104 2.026 100.0

In some embodiments, Form E is characterized by one or more peaks in itsRaman spectrum selected from those in Table 13. In some embodiments,Form E is characterized by at least one, at least two, at least three,at least four, at least five, at least six, at least seven, or at leasteight peaks in its Raman spectrum selected from those in Table 13.

TABLE 13 Select characteristic peaks of the Raman spectrum of Form E.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1606 1.62180.0 1503 0.780 38.5 1448 0.661 32.6 1429 0.749 37.0 1391 0.676 33.41026 0.795 39.2 806 0.723 35.7 789 0.826 40.8

In some embodiments, Form E has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 15.

In some embodiments, Form E is obtained from methanol. In someembodiments, Form E is a methanol solvate. In some embodiments, Form Eis a non-stoichiometric solvate. In some embodiments, Form E is anon-stoichiometric methanol solvate.

Form F

In certain embodiments, the present invention provides crystalline FormF (Form F) of compound 1. In certain embodiments, Form F issubstantially free of impurities. In certain embodiments, Form F is 99%free of impurities by weight. In certain embodiments, Form F is 97% freeof impurities by weight. In certain embodiments, Form F is 95% free ofimpurities by weight. In certain embodiments, Form F is substantiallyfree of amorphous compound 1. In certain embodiments, Form F issubstantially free of other crystalline forms of compound 1. In certainembodiments, Form F is substantially free of a salt of compound 1.

Form F can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form F is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 16. In some embodiments, Form F is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 14. In some embodiments, Form F ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, at least twenty,at least twenty-one, at least twenty-two, at least twenty-three, atleast twenty-four, at least twenty-five, at least twenty-six, at leasttwenty-seven, at least twenty-eight, at least twenty-nine, at leastthirty, at least thirty-one, at least thirty-two, at least thirty-three,or at least thirty-four peaks in its X-ray powder diffraction patternselected from those in Table 14. In some embodiments, Form F of compound1 is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 14.

TABLE 14 X-ray powder diffraction pattern of Form F. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 3.84 23.0 s 41 5.7015.5 m 17 5.97 14.8 m 19 7.02 12.6 vs 100 8.26 10.7 s 38 9.19 9.6 s 3510.21 8.7 w 8 10.62 8.3 w 13 10.98 8.1 w 11 11.34 7.8 m 22 12.07 7.3 m25 12.47 7.1 w 13 13.79 6.4 m 15 14.72 6.0 m 18 15.11 5.86 s 34 16.475.38 m 22 16.70 5.31 m 26 17.81 4.98 m 23 18.41 4.82 s 47 19.74 4.49 m24 20.27 4.38 m 24 20.84 4.26 m 26 21.32 4.16 m 26 21.76 4.08 m 28 23.153.84 s 44 24.04 3.70 m 27 24.43 3.64 m 15 24.87 3.58 m 16 25.60 3.48 m27 26.04 3.42 m 18 26.94 3.31 m 18 30.11 2.97 w 11 30.55 2.92 w 13 31.062.88 w 12

In some embodiments, Form F is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 15. Insome embodiments, Form F is characterized by at least one, at least two,at least three, at least four, at least five, or at least six peaks inits X-ray powder diffraction pattern selected from those in Table 15.

TABLE 15 Select characteristic peaks of the X-ray powder diffractionpattern of Form F. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 7.02 12.6 vs 100 8.26 10.7 s 38 9.19 9.6 s 35 15.11 5.86 s34 18.41 4.82 s 47 23.15 3.84 s 44

In some embodiments, Form F is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 17. In someembodiments, Form F is characterized by one or more peaks in its Ramanspectrum selected from those in Table 16. In some embodiments, Form F ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, or at least ten peaks in its Raman spectrum selected fromthose in Table 16.

TABLE 16 Raman spectrum of Form F. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3360 0.087 4.5 3072 0.516 26.7 3044 0.678 35.02976 0.985 50.9 2963 0.996 51.4 2927 1.498 77.4 2871 0.709 36.6 16051.936 100.0 1502 0.950 49.1 1449 0.768 39.7 1426 0.746 38.5 1390 0.71937.1 1352 0.662 34.2 1323 0.439 22.7 1302 0.354 18.3 1272 0.476 24.61243 0.310 16.0 1208 0.372 19.2 1135 0.239 12.3 1092 0.264 13.6 10610.342 17.7 1024 0.769 39.7 998 0.560 28.9 884 0.214 11.1 852 0.359 18.5808 0.763 39.4 791 0.896 46.3 741 0.387 20.0 721 0.538 27.8 680 0.34818.0 577 0.263 13.6 548 0.335 17.3 484 0.351 18.1 442 0.309 16.0 4080.325 16.8 332 0.308 15.9 256 0.446 23.0 226 0.389 20.1 199 0.613 31.7155 0.585 30.2

In some embodiments, Form F is characterized by one or more peaks in itsRaman spectrum selected from those in Table 17. In some embodiments,Form F is characterized by at least one, at least two, at least three,at least four, at least five, at least six, at least seven, at leasteight, or at least nine peaks in its Raman spectrum selected from thosein Table 17.

TABLE 17 Select characteristic peaks of the Raman spectrum of Form F.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1605 1.936100.0 1502 0.950 49.1 1449 0.768 39.7 1426 0.746 38.5 1390 0.719 37.11352 0.662 34.2 1024 0.769 39.7 808 0.763 39.4 791 0.896 46.3

In some embodiments, Form F has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 18.

In some embodiments, Form F is obtained from ethanol. In someembodiments, Form F is an ethanol solvate. In some embodiments, Form Fis a non-stoichiometric solvate. In some embodiments, Form F is anon-stoichiometric ethanol solvate.

In some embodiments, Form F is stable for at least about 1 month, atleast about 2 months, at least about 4 months, at least about 6 months,at least about 12 months, at least about 18 months, at least about 2years, or at least about 3 years at about 25° C. and about 60% relativehumidity.

Form G

In certain embodiments, the present invention provides crystalline FormG (Form G) of compound 1. In certain embodiments, Form G issubstantially free of impurities. In certain embodiments, Form G is 99%free of impurities by weight. In certain embodiments, Form G is 97% freeof impurities by weight. In certain embodiments, Form G is 95% free ofimpurities by weight. In certain embodiments, Form G is substantiallyfree of amorphous compound 1. In certain embodiments, Form G issubstantially free of other crystalline forms of compound 1. In certainembodiments, Form G is substantially free of a salt of compound 1.

Form G can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form G is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 19. In some embodiments, Form G is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 18. In some embodiments, Form G ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, or at least fourteen peaks in its X-ray powder diffractionpattern selected from those in Table 18. In some embodiments, Form G ofcompound 1 is characterized in that it has one or more peaks in itsX-ray powder diffraction pattern selected from the strong and verystrong peaks in Table 18.

TABLE 18 X-ray powder diffraction pattern of Form G. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 3.54 24.9 vs 1005.00 17.7 m 27 6.12 14.4 m 16 7.08 12.5 m 21 7.89 11.2 vs 93 11.18 7.9 m24 12.75 6.9 m 16 14.17 6.2 m 25 14.60 6.1 s 55 15.82 5.60 s 31 17.735.00 s 42 18.07 4.91 s 48 21.13 4.20 m 27 23.93 3.72 s 30

In some embodiments, Form G is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 19. Insome embodiments, Form G is characterized by at least one, at least two,at least three, or at least four peaks in its X-ray powder diffractionpattern selected from those in Table 19.

TABLE 19 Select characteristic peaks of the X-ray powder diffractionpattern of Form G. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 7.89 11.2 vs 93 14.60 6.1 s 55 17.73 5.00 s 42 18.07 4.91 s48

In some embodiments, Form G is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 20. In someembodiments, Form G is characterized by one or more peaks in its Ramanspectrum selected from those in Table 20. In some embodiments, Form G ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 20.

TABLE 20 Raman spectrum of Form G. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3348 0.083 5.8 3073 0.385 26.8 3039 0.568 39.52967 0.738 51.4 2931 1.038 72.2 2873 0.551 38.3 1604 1.437 100.0 15040.670 46.6 1449 0.496 34.5 1427 0.558 38.8 1391 0.480 33.4 1354 0.46432.3 1323 0.281 19.6 1302 0.247 17.2 1273 0.316 22.0 1244 0.199 13.81209 0.268 18.6 1155 0.157 10.9 1124 0.152 10.6 1090 0.185 12.9 10620.235 16.4 1026 0.515 35.8 998 0.319 22.2 917 0.134 9.3 852 0.245 17.0808 0.395 27.5 791 0.552 38.4 740 0.278 19.3 719 0.325 22.6 680 0.23416.3 579 0.187 13.0 550 0.188 13.1 482 0.213 14.8 442 0.179 12.5 3960.209 14.5 332 0.215 15.0 258 0.268 18.6 201 0.351 24.4

In some embodiments, Form G is characterized by one or more peaks in itsRaman spectrum selected from those in Table 21. In some embodiments,Form G is characterized by at least one, at least two, at least three,at least four, at least five, at least six, at least seven, or at leasteight peaks in its Raman spectrum selected from those in Table 21.

TABLE 21 Select characteristic peaks of the Raman spectrum of Form G.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1604 1.437100.0 1504 0.670 46.6 1449 0.496 34.5 1427 0.558 38.8 1391 0.480 33.41354 0.464 32.3 1026 0.515 35.8 791 0.552 38.4

In some embodiments, Form G has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 21.

In some embodiments, Form G is obtained from isopropanol. In someembodiments, Form G is an isopropanol solvate. In some embodiments, FormG is a non-stoichiometric solvate. In some embodiments, Form G is anon-stoichiometric isopropanol solvate.

Form H

In certain embodiments, the present invention provides crystalline FormH (Form H) of compound 1.

In certain embodiments, Form H is substantially free of impurities. Incertain embodiments, Form H is 99% free of impurities by weight. Incertain embodiments, Form H is 97% free of impurities by weight. Incertain embodiments, Form H is 95% free of impurities by weight. Incertain embodiments, Form H is substantially free of amorphouscompound 1. In certain embodiments, Form H is substantially free ofother crystalline forms of compound 1. In certain embodiments, Form H issubstantially free of a salt of compound 1.

Form H can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form H is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 22. In some embodiments, Form H is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 22. In some embodiments, Form H ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, or at leastthirteen peaks in its X-ray powder diffraction pattern selected fromthose in Table 22. In some embodiments, Form H of compound 1 ischaracterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 22.

TABLE 22 X-ray powder diffraction pattern of Form H. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 3.58 24.7 vs 1006.13 14.4 s 52 7.50 11.8 s 68 7.87 11.2 vs 81 9.96 8.9 m 29 11.17 7.9 s31 12.73 6.9 s 50 14.10 6.3 s 41 14.59 6.1 s 56 15.68 5.65 vs 85 17.695.01 s 66 18.79 4.72 s 57 21.84 4.07 s 61

In some embodiments, Form H is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 23. Insome embodiments, Form H is characterized by at least one, at least two,at least three, at least four, or at least five peaks in its X-raypowder diffiaction pattern selected from those in Table 23.

TABLE 23 Select characteristic peaks of the X-ray powder diffractionpattern of Form H. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 6.13 14.4 s 52 7.87 11.2 vs 81 12.73 6.9 s 50 15.68 5.65 vs85 17.69 5.01 s 66

In some embodiments, Form II is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 23. In someembodiments, Form H is characterized by one or more peaks in its Ramanspectrum selected from those in Table 24. In some embodiments, Form H ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 24,

TABLE 24 Raman spectrum of Form H. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3324 0.093 4.8 3074 0.457 23.7 3041 0.769 39.82976 1.070 55.4 2931 1.027 53.2 2873 0.793 41.1 1627 0.918 47.5 16041.931 100.0 1503 0.845 43.8 1448 0.659 34.1 1427 0.743 38.5 1394 0.57029.5 1347 0.614 31.8 1323 0.317 16.4 1302 0.356 18.4 1273 0.364 18.91246 0.289 15.0 1211 0.346 17.9 1125 0.197 10.2 1090 0.237 12.3 10620.322 16.7 1035 0.403 20.9 1027 0.606 31.4 1009 0.295 15.3 997 0.35818.5 942 0.182 9.4 854 0.364 18.9 822 0.250 12.9 808 0.378 19.6 7910.671 34.7 740 0.455 23.6 719 0.333 17.2 680 0.298 15.4 579 0.262 13.6550 0.224 11.6 480 0.268 13.9 466 0.258 13.4 439 0.238 12.3 396 0.31516.3 327 0.324 16.8 260 0.373 19.3 191 0.409 21.2

In some embodiments, Form H is characterized by one or more peaks in itsRaman spectrum selected from those in Table 25. In some embodiments,Form H is characterized by at least one, at least two, at least three,at least four, at least five, at least six, at least seven, or at leasteight peaks in its Raman spectrum selected from those in Table 25.

TABLE 25 Select characteristic peaks of the Raman spectrum of Form H.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1627 0.91847.5 1601 1.931 100.0 1503 0.845 43.8 1448 0.659 34.1 1427 0.743 38.51347 0.614 31.8 1027 0.606 31.4 791 0.671 34.7

In some embodiments, Form H has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 24.

In some embodiments, Form H is obtained from 1-butanol. In someembodiments, Form H is a 1-butanol solvate. In some embodiments, Form His a non-stoichiometic solvate. In some embodiments, Form H is anon-stoichiometric I-butanol solvate

Form I

In certain embodiments, the present invention provides crystalline FormI of compound 1. In certain embodiments, Form I is substantially free ofimpurities. In certain embodiments, Form I is 99% free of impurities byweight. In certain embodiments, Form I is 97% free of impurities byweight. In certain embodiments, Form I is 95% free of impurities byweight. In certain embodiments, Form I is substantially free ofamorphous compound 1. In certain embodiments, Form I is substantiallyfree of other crystalline forms of compound 1. In certain embodiments,Form I is substantially free of a salt of compound 1.

Form I can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form I is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 25. In some embodiments, Form I is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 26. In some embodiments, Form I ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, or at least nineteen peaks in itsX-ray powder diffraction pattern selected from those in Table 26. Insome embodiments, Form I of compound 1 is characterized in that it hasone or more peaks in its X-ray powder diffraction pattern selected fromthe strong and very strong peaks in Table 26.

TABLE 26 X-ray powder diffraction pattern of Form I. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 3.81 23.1 vs 99 5.2316.9 s 33 6.24 14.2 vs 83 7.57 11.7 vs 85 8.02 11.0 s 47 8.74 10.1 s 649.34 9.5 s 38 10.01 8.8 s 32 12.45 7.1 s 42 12.88 6.9 s 64 14.09 6.3 s58 16.03 5.52 vs 100 17.48 5.07 vs 75 18.70 4.74 vs 81 21.40 4.15 s 4321.90 4.05 s 46 22.48 3.95 s 47 24.12 3.69 s 44 25.71 3.46 s 34

In some embodiments, Form I is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 27. Insome embodiments, Form I is characterized by at least one, at least two,at least three, at least four, at least five, or at least six peaks inits X-ray powder diffraction pattern selected from those in Table 27.

TABLE 27 Select characteristic peaks of the X-ray powder diffractionpattern of Form I. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 6.24 14.2 vs 83 7.57 11.7 vs 85 8.74 10.1 s 64 16.03 5.52 vs100 17.48 5.07 vs 75 18.70 4.74 vs 81

In some embodiments, Form I is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 26. In someembodiments, Form I is characterized by one or more peaks in its Ramanspectrum selected from those in Table 28. In some embodiments, Form I ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 28.

TABLE 28 Raman spectrum of Form I. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3072 0.111 18.7 3040 0.193 32.5 2976 0.286 48.22930 0.263 44.4 2873 0.191 32.2 1628 0.338 57.0 1603 0.593 100.0 15020.277 46.7 1448 0.208 35.1 1427 0.243 41.0 1394 0.183 30.9 1376 0.09916.7 1347 0.209 35.2 1322 0.094 15.9 1302 0.105 17.7 1279 0.116 19.61245 0.095 16.0 1221 0.095 16.0 1210 0.116 19.6 1158 0.058 9.8 11220.062 10.5 1089 0.076 12.8 1062 0.105 17.7 1027 0.212 35.8 1008 0.10016.9 997 0.122 20.6 943 0.059 9.9 916 0.081 13.7 854 0.124 20.9 8210.080 13.5 807 0.117 19.7 791 0.226 38.1 739 0.166 28.0 718 0.110 18.5681 0.104 17.5 579 0.095 16.0 540 0.077 13.0 520 0.076 12.8 480 0.09516.0 466 0.092 15.5 439 0.088 14.8 419 0.092 15.5 395 0.121 20.4 3570.081 13.7 325 0.122 20.6 259 0.140 23.6 190 0.173 29.2

In some embodiments, Form I is characterized by one or more peaks in itsRaman spectrum selected from those in Table 29. In some embodiments,Form I is characterized by at least one, at least two, at least three,at least four, at least five, at least six, at least seven, at leasteight, or at least nine peaks in its Raman spectrum selected from thosein Table 29.

TABLE 29 Select characteristic peaks of the Raman spectrum of Form I.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1628 0.33857.0 1603 0.593 100.0 1502 0.277 46.7 1448 0.208 35.1 1427 0.243 41.01394 0.183 30.9 1347 0.209 35.2 1027 0.212 35.8 791 0.226 38.1

In some embodiments, Form I has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 27.

In some embodiments, Form I is obtained from tetrahydrofuran. In someembodiments, Form I is a tetrahydrofuran solvate. In some embodiments,Form I is a non-stoichiometric solvate. In some embodiments, Form I is anon-stoichiometric tetrahydrofuran solvate.

Form J

In certain embodiments, the present invention provides crystalline FormJ of compound 1. In certain embodiments, Form J is substantially free ofimpurities. In certain embodiments, Form J is 99% free of impurities byweight. In certain embodiments, Form J is 97% free of impurities byweight. In certain embodiments, Form J is 95% free of impurities byweight. In certain embodiments, Form J is substantially free ofamorphous compound 1. In certain embodiments, Form J is substantiallyfree of other crystalline forms of compound 1. In certain embodiments,Form J is substantially free of a salt of compound 1.

Form J can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form J is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 28. In some embodiments, Form J is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 30. In some embodiments, Form J ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, at least twenty,at least twenty-one, at least twenty-two, at least twenty-three, atleast twenty-four, at least twenty-five, at least twenty-six, at leasttwenty-seven, at least twenty-eight, at least twenty-nine, at leastthirty, at least thirty-one, at least thirty-two, at least thirty-three,at least thirty-four, at least thirty-five, at least thirty-six, atleast thirty-seven, at least thirty-eight, at least thirty-nine, atleast forty, at least forty-one, at least forty-two, at leastforty-three, at least forty-four, at least forty-five, at leastforty-six, at least forty-seven, at least forty-eight, at leastforty-nine, at least fifty, fifty-one, at least fifty-two, at leastfifty-three, at least fifty-four, at least fifty-five, at leastfifty-six, at least fifty-seven, at least fifty-eight, at leastfifty-nine, at least sixty peaks in its X-ray powder diffraction patternselected from those in Table 30. In some embodiments, Form J of compound1 is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 30.

TABLE 30 X-ray powder diffraction pattern of Form J. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 6.26 14.1 vs 1008.12 10.9 vw 3 8.83 10.0 vw 2 9.12 9.7 vw 2 9.33 9.5 w 5 10.04 8.8 m 2112.21 7.2 vw 5 12.57 7.0 vw 2 12.80 6.9 vw 2 12.97 6.8 vw 4 13.20 6.7 m17 14.54 6.1 w 9 14.73 6.0 vw 4 15.38 5.76 w 6 15.75 5.62 vw 4 16.325.43 w 5 16.46 5.38 vw 4 16.90 5.24 vw 4 17.11 5.18 vw 2 17.50 5.06 vw 217.76 4.99 vw 4 18.13 4.89 w 8 18.38 4.82 w 13 18.62 4.76 w 8 18.88 4.70w 13 19.07 4.65 vw 4 19.98 4.44 vw 5 20.21 4.39 w 14 20.62 4.30 w 521.15 4.20 w 7 21.48 4.13 vw 3 21.93 4.05 vw 4 22.24 3.99 vw 4 22.753.91 vw 3 23.16 3.84 vw 4 23.34 3.81 w 9 23.67 3.76 vw 2 24.10 3.69 w 624.54 3.62 w 7 24.84 3.58 vw 2 25.11 3.54 vw 3 25.28 3.52 vw 3 25.603.48 w 8 25.87 3.44 w 6 26.10 3.41 vw 3 26.59 3.35 vw 2 27.25 3.27 vw 227.67 3.22 vw 2 28.05 3.18 vw 3 28.60 3.12 vw 2 28.95 3.08 vw 2 29.283.05 vw 3 29.59 3.02 vw 2 29.86 2.99 vw 2 30.63 2.92 vw 2 31.78 2.81 vw3 32.53 2.75 vw 2 32.80 2.73 vw 2 32.96 2.72 vw 2 33.23 2.69 vw 3

In some embodiments, Form J is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 31. Insome embodiments, Form J is characterized by at least one, at least two,at least three, at least four, at least five, or at least six peaks inits X-ray powder diffraction pattern selected from those in Table 31.

TABLE 31 Select characteristic peaks of the X-ray powder diffractionpattern of Form J. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 6.26 14.1 vs 100 10.04 8.8 m 21 13.20 6.7 m 17 18.38 4.82 w13 18.88 4.70 w 13 20.21 4.39 w 14

In some embodiments, Form J is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 29. In someembodiments, Form J is characterized by one or more peaks in its Ramanspectrum selected from those in Table 32. In some embodiments, Form J ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 32.

TABLE 32 Raman spectrum of Form J. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3293 0.192 4.3 3070 0.563 12.8 3034 1.175 26.62977 0.934 21.2 2955 1.121 25.4 2933 1.197 27.1 2899 1.219 27.6 28640.780 17.7 2843 0.558 12.6 1610 3.336 75.6 1593 4.414 100.0 1483 1.05924.0 1465 0.954 21.6 1442 1.264 28.6 1397 0.304 6.9 1367 0.479 10.9 13350.516 11.7 1300 0.707 16.0 1278 0.633 14.3 1261 0.536 12.1 1208 0.4229.6 1138 0.260 5.9 1096 0.310 7.0 1060 0.241 5.5 1026 0.781 17.7 10030.342 7.7 987 0.432 9.8 852 0.483 10.9 785 1.087 24.6 780 1.120 25.4 7461.028 23.3 713 0.438 9.9 687 0.460 10.4 584 0.284 6.4 487 0.390 8.8 4130.170 3.9 343 0.191 4.3 238 0.441 10.0 193 0.340 7.7 142 0.655 14.8

In some embodiments, Form J is characterized by one or more peaks in itsRaman spectrum selected from those in Table 33. In some embodiments,Form J is characterized by at least one, at least two, at least three,at least four, at least five, at least six, at least seven, or at leasteight peaks in its Raman spectrum selected from those in Table 33.

TABLE 33 Select characteristic peaks of the Raman spectrum of Form J.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1610 3.33675.6 1593 4.414 100.0 1483 1.059 24.0 1465 0.954 21.6 1442 1.264 28.6785 1.087 24.6 780 1.120 25.4 746 1.028 23.3

In some embodiments, Form J has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 30. In some embodiments, Form J isobtained from ethyl acetate. In some embodiments, Form J is an ethylacetate solvate. In some embodiments, Form J is a non-stoichiometricsolvate. In some embodiments, Form J is a non-stoichiometric ethylacetate solvate.

Form K

In certain embodiments, the present invention provides crystalline FormK (Form K) of compound 1. In certain embodiments, Form K issubstantially free of impurities. In certain embodiments, Form K is 99%free of impurities by weight. In certain embodiments, Form K is 97% freeof impurities by weight. In certain embodiments, Form K is 95% free ofimpurities by weight. In certain embodiments, Form K is substantiallyfree of amorphous compound 1. In certain embodiments, Form K issubstantially free of other crystalline forms of compound 1. In certainembodiments, Form K is substantially free of a salt of compound 1.

Form K can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form K is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 31. In some embodiments, Form K is characterized inthat it has one or more peaks in its X-ray powder diffiaction patternselected from those in Table 34. In some embodiments, Form K ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, or at leasttwenty peaks in its X-ray powder diffraction pattern selected from thosein Table 34. In some embodiments, Form K of compound 1 is characterizedin that it has one or more peaks in its X-ray powder diffraction patternselected from the strong and very strong peaks in Table 34.

TABLE 34 X-ray powder diffraction pattern of Form K. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 3.55 24.9 s 42 5.8915.0 s 43 6.94 12.7 s 43 7.18 12.3 s 53 8.47 10.4 s 39 9.00 9.8 m 2210.20 8.7 m 22 10.82 8.2 m 17 12.55 7.0 m 23 14.11 6.3 s 34 14.67 6.0 s54 15.36 5.77 s 43 15.87 5.58 s 51 17.19 5.16 vs 77 17.82 4.97 vs 8618.08 4.90 s 69 19.68 4.51 vs 100 20.78 4.27 s 44 21.97 4.04 s 45 22.273.99 s 45

In some embodiments, Form K is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 35. Insome embodiments, Form K is characterized by at least one, at least two,at least three, at least four, at least five, at least six, or at leastseven peaks in its X-ray powder diffraction pattern selected from thosein Table 35.

TABLE 35 Select characteristic peaks of the X-ray powder diffractionpattern of Form K. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 7.18 12.3 s 53 14.67 6.0 s 54 15.87 5.58 s 51 17.19 5.16 vs77 17.82 4.97 vs 86 18.08 4.90 s 69 19.68 4.51 vs 100

In some embodiments, Form K is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 32. In someembodiments, Form K is characterized by one or more peaks in its Ramanspectrum selected from those in Table 36. In some embodiments, Form K ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 36.

TABLE 36 Raman spectrum of Form K. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3338 0.082 3.8 3074 0.375 17.5 3040 0.492 22.92967 1.134 52.8 2931 0.919 42.8 2857 0.638 29.7 2720 0.202 9.4 16002.148 100.0 1503 0.711 33.1 1481 0.490 22.8 1446 0.723 33.7 1427 0.64830.2 1390 0.555 25.8 1352 0.537 25.0 1340 0.512 23.8 1325 0.453 21.11305 0.479 22.3 1275 0.463 21.6 1218 0.386 18.0 1128 0.258 12.0 10900.273 12.7 1061 0.326 15.2 1027 0.642 29.9 1017 0.455 21.2 998 0.43420.2 852 0.376 17.5 836 0.701 32.6 808 0.570 26.5 789 0.765 35.6 7420.426 19.8 719 0.467 21.7 680 0.346 16.1 578 0.274 12.8 549 0.315 14.7487 0.386 18.0 442 0.335 15.6 409 0.356 16.6 394 0.357 16.6 332 0.38117.7 258 0.492 22.9 228 0.431 20.1 199 0.536 25.0

In some embodiments, Form K is characterized by one or more peaks in itsRaman spectrum selected from those in Table 37. In some embodiments,Form K is characterized by at least one, at least two, at least three,at least four, at least five, or at least six peaks in its Ramanspectrum selected from those in Table 37.

TABLE 37 Select characteristic peaks of the Raman spectrum of Form K.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1600 2.148100.0 1503 0.711 33.1 1446 0.723 33.7 1427 0.648 30.2 836 0.701 32.6 7890.765 35.6

In some embodiments, Form K has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 33. In some embodiments, Form K isobtained from dioxane. In some embodiments, Form K is a dioxane solvate.In some embodiments, Form K is a non-stoichiometric solvate. In someembodiments, Form K is a non-stoichiometric dioxane solvate.

Form L

In certain embodiments, the present invention provides crystalline FormL of compound 1. In certain embodiments, Form L is substantially free ofimpurities. In certain embodiments, Form L is 99% free of impurities byweight. In certain embodiments, Form L is 97% free of impurities byweight. In certain embodiments, Form L is 95% free of impurities byweight. In certain embodiments, Form L is substantially free ofamorphous compound 1. In certain embodiments, Form L is substantiallyfree of other crystalline forms of compound 1. In certain embodiments,Form L is substantially free of a salt of compound 1.

Form L can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form L is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 34. In some embodiments, Form L is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 38. In some embodiments, Form L ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, or at least nineteen peaks in itsX-ray powder diffraction pattern selected from those in Table 38. Insome embodiments, Form L of compound 1 is characterized in that it hasone or more peaks in its X-ray powder diffraction pattern selected fromthe strong and very strong peaks in Table 38.

TABLE 38 X-ray powder diffraction pattern of Form L. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 4.07 21.7 m 20 5.9814.8 s 59 8.31 10.6 s 37 8.54 10.3 s 34 9.39 9.4 s 55 12.02 7.4 s 3415.31 5.78 vs 100 17.27 5.13 s 31 17.76 4.99 s 44 18.84 4.71 s 37 19.284.60 s 55 20.13 4.41 m 19 21.19 4.19 s 36 21.49 4.13 s 49 21.91 4.05 s35 23.04 3.86 m 25 23.68 3.75 m 30 24.45 3.64 m 26 26.98 3.30 m 29

In some embodiments, Form L is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 39. Insome embodiments, Form L is characterized by at least one, at least two,at least three, at least four, at least five, or at least six peaks inits X-ray powder diffraction pattern selected from those in Table 39,

TABLE 39 Select characteristic peaks of the X-ray powder diffractionpattern of Form L. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 5.98 14.8 s 59 9.39 9.4 s 55 15.31 5.78 vs 100 17.76 4.99 s44 19.28 4.60 s 55 21.49 4.13 s 49

In some embodiments, Form L is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 35. In someembodiments, Form L is characterized by one or more peaks in its Ramanspectrum selected from those in Table 40. In some embodiments, Form L ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 40.

TABLE 40 Raman spectrum of Form L. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3316 0.093 5.6 3049 0.715 43.1 2975 1.133 68.32931 0.643 38.8 2909 0.680 41.0 2872 0.572 34.5 1626 1.197 72.2 16111.659 100.0 1603 1.630 98.3 1589 1.224 73.8 1502 0.803 48.4 1474 0.35721.5 1447 0.667 40.2 1427 0.752 45.3 1395 0.592 35.7 1376 0.303 18.31345 0.743 44.8 1281 0.316 19.0 1245 0.271 16.3 1229 0.300 18.1 12110.383 23.1 1157 0.200 12.1 1133 0.207 12.5 1090 0.228 13.7 1061 0.31318.9 1031 0.553 33.3 1010 0.342 20.6 992 0.406 24.5 941 0.184 11.1 9240.158 9.5 869 0.284 17.1 853 0.293 17.7 821 0.246 14.8 808 0.201 12.1791 0.625 37.7 740 0.469 28.3 714 0.331 20.0 681 0.288 17.4 586 0.24114.5 540 0.248 14.9 522 0.224 13.5 493 0.261 15.7 464 0.267 16.1 4380.270 16.3 417 0.257 15.5 394 0.326 19.7 356 0.234 14.1 326 0.365 22.0247 0.334 20.1 212 0.375 22.6 188 0.485 29.2

In some embodiments, Form L is characterized by one or more peaks in itsRaman spectrum selected from those in Table 41. In some embodiments,Form L is characterized by at least one, at least two, at least three,at least four, at least five, at least six, at least seven, at leasteight, at least nine, at least ten, or at least eleven peaks in itsRamnan spectrum selected from those in Table 41.

TABLE 41 Select characteristic peaks of the Raman spectrum of Form L.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1626 1.19772.2 1611 1.659 100.0 1603 1.630 98.3 1589 1.224 73.8 1502 0.803 48.41447 0.667 40.2 1427 0.752 45.3 1395 0.592 35.7 1345 0.743 44.8 10310.553 33.3 791 0.625 37.7

In some embodiments, Form L has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 36. In some embodiments, Form L isobtained from pyridine/hexane. In some embodiments, Form L is a pyridinesolvate. In some embodiments, Form L is a non-stoichiometric solvate. Insome embodiments, Form L is a non-stoichiometric pyridine solvate.

Form M

In certain embodiments, the present invention provides crystalline FormM of compound 1. In certain embodiments, Form M is substantially free ofimpurities. In certain embodiments, Form M is 99% free of impurities byweight. In certain embodiments, Form M is 97% free of impurities byweight. In certain embodiments, Form M is 95% free of impurities byweight. In certain embodiments, Form M is substantially free ofamorphous compound 1. In certain embodiments, Form M is substantiallyfree of other crystalline forms of compound 1. In certain embodiments,Form M is substantially free of a salt of compound 1.

Form M can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form M is characterizedby an X-ray powder diffraction pattern substantially similar to the onedepicted in FIG. 37. In some embodiments, Form M is characterized inthat it has one or more peaks in its X-ray powder diffraction patternselected from those in Table 42. In some embodiments, Form M ischaracterized by at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, at least twenty,at least twenty-one, at least twenty-two, at least twenty-three, atleast twenty-four, at least twenty-five, at least twenty-six, at leasttwenty-seven, at least twenty-eight, at least twenty-nine, at leastthirty, at least thirty-one, at least thirty-two, at least thirty-three,at least thirty-four, at least thirty-five, at least thirty-six, atleast thirty-seven, at least thirty-eight, at least thirty-nine, or atleast forty peaks in its X-ray powder diffraction pattern selected fromthose in Table 42. In some embodiments, Form M of compound 1 ischaracterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 42.

TABLE 42 X-ray powder diffraction pattern of Form M. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 5.64 15.7 w 6 6.1314.4 vw 2 7.67 11.5 vw 5 11.26 7.8 vs 100 11.98 7.4 vw 3 12.26 7.2 vw 213.66 6.5 vw 2 14.27 6.2 vw 2 15.35 5.77 w 13 16.61 5.33 w 5 16.94 5.23s 61 17.12 5.17 m 20 17.96 4.94 s 36 18.45 4.80 w 10 18.92 4.69 vw 519.38 4.58 m 16 19.80 4.48 vw 4 20.13 4.41 m 16 20.87 4.25 m 16 21.284.17 w 8 21.81 4.07 vw 4 21.96 4.04 w 8 22.64 3.92 s 51 23.14 3.84 w 1124.43 3.64 m 16 24.78 3.59 w 12 25.30 3.52 vw 5 25.56 3.48 w 5 27.043.29 w 8 27.37 3.26 vw 4 27.65 3.22 vw 4 28.15 3.17 vw 4 28.50 3.13 vw 429.32 3.04 vw 3 30.06 2.97 vw 4 32.41 2.76 vw 2 32.85 2.72 vw 3 33.902.64 vw 2 34.33 2.61 vw 4 34.70 2.58 vw 3

In some embodiments, Form M is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those in Table 43. Insome embodiments, Form M is characterized by at least one, at least two,at least three, at least four, at least five, at least six, or at leastseven peaks in its X-ray powder diffraction pattern selected from thosein Table 43.

TABLE 43 Select characteristic peaks of the X-ray powder diffractionpattern of Form M. Angle d value Intensity 2-Theta ° Angstrom (relative)Intensity % 11.26 7.8 vs 100 16.94 5.23 s 61 17.96 4.94 s 36 19.38 4.58m 16 20.13 4.41 m 16 20.87 4.25 m 16 22.64 3.92 s 51

In some embodiments, Form M is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 38. In someembodiments, Form M is characterized by one or more peaks in its Ramanspectrum selected from those in Table 44. In some embodiments, Form M ischaracterized by having a Raman spectrum with characteristic peaks atabout those in Table 44.

TABLE 44 Raman spectrum of Form M. Wavenumber Absolute Normalized (cm⁻¹)Intensity Intensity (%) 3315 0.044 3.2 3073 0.267 19.7 3046 0.282 20.83012 0.266 19.6 2990 0.487 35.9 2965 0.436 32.2 2946 0.384 28.3 29130.860 63.4 2846 0.275 20.3 1629 0.529 39.0 1608 1.356 100.0 1501 0.60044.2 1470 0.200 14.7 1446 0.338 24.9 1429 0.491 36.2 1393 0.329 24.31349 0.352 26.0 1318 0.141 10.4 1305 0.126 9.3 1284 0.146 10.8 12690.152 11.2 1245 0.132 9.7 1227 0.184 13.6 1210 0.181 13.3 1197 0.089 6.61146 0.107 7.9 1135 0.120 8.8 1095 0.103 7.6 1059 0.138 10.2 1035 0.20615.2 1027 0.279 20.6 1018 0.274 20.2 1010 0.199 14.7 991 0.203 15.0 9520.067 4.9 915 0.064 4.7 862 0.131 9.7 847 0.222 16.4 821 0.075 5.5 7860.359 26.5 740 0.420 31.0 711 0.172 12.7 703 0.185 13.6 676 0.519 38.3597 0.123 9.1 585 0.075 5.5 546 0.070 5.2 483 0.121 8.9 468 0.087 6.4443 0.077 5.7 422 0.116 8.6 413 0.074 5.5 389 0.127 9.4 337 0.226 16.7313 0.137 10.1 262 0.172 12.7 228 0.148 10.9 206 0.186 13.7 190 0.23617.4 108 1.010 74.5

In some embodiments, Form M is characterized by one or more peaks in itsRaman spectrum selected from those in Table 45. In some embodiments,Form M is characterized by at least one, at least two, at least three,at least four, at least five, or at least six peaks in its Ramanspectrum selected from those in Table 45.

TABLE 45 Select characteristic peaks of the Raman spectrum of Form M.Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%) 1629 0.52939.0 1608 1.356 100.0 1501 0.600 44.2 1429 0.491 36.2 740 0.420 31.0 6760.519 38.3

In some embodiments, Form M has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 39. In some embodiments, Form M isobtained from dimethylsulfoxide/tert-butyl methyl ether. In someembodiments, Form M is a dimethylsulfoxide (DMSO) solvate. In someembodiments, Form M is a non-stoichiometric solvate. In someembodiments, Form M is a non-stoichiometric DMSO solvate.

Fumarate Salt, Co-Crystal, and Form FUM-P3

The present invention also provides various salts or salt forms ofcompound 1. In certain embodiments, provided is a fumarate salt form ofcompound 1. The fumarate salt may be amorphous or exist in one or morecrystalline forms. In certain embodiments, the present inventionprovides a crystalline form of compound 1, designated Form FUM-P3. Insome embodiments, Form FUM-P3 is a salt of compound 1. In someembodiments, Form FUM-P3 is a fumarate salt of compound 1. In someembodiments, Form FUM-P3 is a hemifumarate salt of compound 1.

The present invention also provides co-crystals of compound 1 andfumaric acid. The primary distinction between a salt form of compound 1and a co-crystal of compound 1 and an additional compound is that in thesalt form compound 1 is ionized and complexed with the salt former in away that proton transfer can easily occur. In the co-crystal, however,compound 1 is complexed with the additional compound in a way thationization of compound 1 and proton transfer are not required.Co-crystals described herein may be useful to improve the properties(e.g., aqueous solubility, stability, and ease of formulation) ofcompound 1. In some embodiments, Form FUM-P3 is a co-crystal of compound1 and fumaric acid.

In certain embodiments, Form FUM-P3 is substantially free of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form FUM-P3 is 99% free of impurities by weight. Incertain embodiments, Form FUM-P3 is 97% free of impurities by weight. Incertain embodiments, Form FUM-P3 is 95% free of impurities by weight. Incertain embodiments, Form FUM-P3 is substantially free ofamorphousfumarate salt of compound 1. In certain embodiments, FormFUM-P3 is substantially free of other crystalline forms of the fumaratesalt of compound 1.

Form FUM-P3 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form FUM-P3 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 40. In some embodiments, Form FUM-P3is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from those in Table 46. In someembodiments, Form FUM-P3 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, at least twenty-seven, at least twenty-eight, at leasttwenty-nine, at least thirty, at least thirty-one, at least thirty-two,at least thirty-three, at least thirty-four, at least thirty-five, atleast thirty-six, at least thirty-seven, at least thirty-eight, or atleast thirty-nine peaks in its X-ray powder diffraction pattern selectedfrom those in Table 46. In some embodiments, Form FUM-P3 of compound 1is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 46.

TABLE 46 Peaks from X-ray powder diffraction pattern. Angle d valueIntensity 2-Theta ° Angstrom (relative) Intensity % 4.48 19.7 m 23 5.3916.4 w 7 6.08 14.5 w 13 7.25 12.2 m 18 7.43 11.9 m 20 7.84 11.3 w 108.84 10.0 w 15 9.02 9.8 w 13 10.00 8.8 w 9 10.79 8.2 m 23 12.16 7.3 m 1712.51 7.1 w 9 13.31 6.6 s 34 14.32 6.2 w 10 14.89 5.94 m 16 15.31 5.78 w13 16.32 5.43 s 30 17.70 5.01 vs 100 18.41 4.82 m 27 19.00 4.67 m 1719.84 4.47 s 32 20.08 4.42 s 46 20.47 4.34 m 20 21.13 4.20 s 48 21.564.12 m 27 21.73 4.09 m 28 22.02 4.03 m 28 22.57 3.94 m 19 23.10 3.85 s40 23.56 3.77 s 37 24.33 3.66 m 20 24.75 3.59 m 26 24.94 3.57 m 22 25.193.53 m 20 25.57 3.48 m 17 26.54 3.36 w 12 27.97 3.19 m 15 28.99 3.08 w12 29.74 3.00 w 9

In some embodiments, Form FUM-P3 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 47.In some embodiments, Form FUM-P3 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,or at least seven peaks in its X-ray powder diffraction pattern selectedfrom those in Table 47.

TABLE 47 Selected characteristic peaks from X-ray powder diffractionpattern of Form FUM-P3 Angle d value Intensity 2-Theta ° Angstrom(relative) Intensity % 13.31 6.6 s 34 17.70 5.01 vs 100 19.84 4.47 s 3220.08 4.42 s 46 21.13 4.20 s 48 23.10 3.85 s 40 23.56 3.77 s 37

In some embodiments, Form FUM-P3 is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 41. In someembodiments, Form FUM-P3 is characterized by one or more peaks in itsRaman spectrum selected from those in Table 48. In some embodiments,Form FUM-P3 is characterized by having a Raman spectrum withcharacteristic peaks at about those wavenumbers listed in Table 48.

TABLE 48 Raman spectrum. Wavenumber Absolute Normalized (cm⁻¹) IntensityIntensity (%) 3074 0.199 23.4 3044 0.164 19.3 3023 0.158 18.6 2994 0.22826.8 2966 0.287 33.7 2949 0.248 29.1 2917 0.332 39.0 2877 0.194 22.82852 0.173 20.3 1720 0.237 27.8 1655 0.124 14.6 1627 0.443 52.1 16090.851 100.0 1596 0.506 59.5 1504 0.303 35.6 1486 0.184 21.6 1460 0.14517.0 1447 0.264 31.0 1430 0.332 39.0 1393 0.283 33.3 1378 0.126 14.81352 0.316 37.1 1318 0.108 12.7 1308 0.108 12.7 1286 0.123 14.5 12720.124 14.6 1258 0.095 11.2 1246 0.124 14.6 1227 0.153 18.0 1209 0.14116.6 1196 0.068 8.0 1147 0.074 8.7 1135 0.101 11.9 1115 0.069 8.1 10590.094 11.0 1037 0.098 11.5 1027 0.175 20.6 1020 0.191 22.4 1011 0.15618.3 992 0.133 15.6 954 0.049 5.8 913 0.044 5.2 891 0.055 6.5 862 0.12214.3 850 0.174 20.4 821 0.070 8.2 789 0.328 38.5 741 0.326 38.3 7130.123 14.5 681 0.118 13.9 602 0.066 7.8 584 0.067 7.9 561 0.052 6.1 5440.060 7.1 491 0.093 10.9 469 0.094 11.0 441 0.098 11.5 422 0.101 11.9411 0.089 10.5 399 0.094 11.0 322 0.113 13.3 267 0.144 16.9 234 0.14416.9 207 0.146 17.2 187 0.231 27.1 130 0.571 67.1

In some embodiments, Form FUM-P3 is characterized by one or more peaksin its Raman spectrum selected from those in Table 49. In someembodiments, Form FUM-P3 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, or at least ten peaks in its Ramanspectrum selected from those in Table 49.

TABLE 49 Select characteristic peaks of the Raman spectrum of FormFUM-P3. Wavenumber Absolute Normalized (cm⁻¹) Intensity Intensity (%)1627 0.443 52.1 1609 0.851 100.0 1596 0.506 59.5 1504 0.303 35.6 14470.264 31.0 1430 0.332 39.0 1393 0.283 33.3 1352 0.316 37.1 789 0.32838.5 741 0.326 38.3

In some embodiments, Form FUM-P3 is characterized by a DSC thermogramsubstantially similar to the one depicted in FIG. 42.

In some embodiments, Form FUM-P3 is characterized by a DVS isothermsubstantially similar to the one depicted in FIG. 43.

In some embodiments, Form FUM-P3 is characterized by a TG-FTIRthermogram substantially similar to the one depicted in FIG. 44.

In some embodiments, Form FUM-P3 is a solvate. In some embodiments, FormFUM-P3 is a hemisolvate. In some embodiments, Form FUM-P3 is anon-stoichiometric solvate. In some embodiments, Form FUM-P3 is obtainedby recrystallization of the fumarate salt of compound 1 from acetone. Insome embodiments, Form FUM-P3 is an acetone solvate.

Form FUM-P4

In certain embodiments, the present invention provides crystalline FormFUM-P4 (Form FUM-P4) of compound 1. In some embodiments, Form FUM-P4 isa salt of compound 1. In some embodiments, Form FUM-P4 is a fumaratesalt of compound 1. In some embodiments, Form FUM-P4 is a mono-fumaratesalt of compound 1. In some embodiments, Form FUM-P4 is a co-crystal ofcompound 1 and fumaric acid.

In certain embodiments, Form FUM-P4 is substantially free of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form FUM-P4 is 99% free of impurities by weight. Incertain embodiments, Form FUM-P4 is 97% free of impurities by weight. Incertain embodiments, Form FUM-P4 is 95% free of impurities by weight. Incertain embodiments, Form FUM-P4 is substantially free of amorphouscompound 1. In certain embodiments, Form FUM-P4 is substantially free ofother crystalline forms of compound 1.

Form FUM-P4 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form FUM-P4 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 45. In some embodiments, Form FUM-P4is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from those in Table 50. In someembodiments, Form FUM-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, or at least twenty-four peaks in its X-ray powderdiffraction pattern selected from those in Table 50. In someembodiments, Form FUM-P4 of compound 1 is characterized in that it hasone or more peaks in its X-ray powder diffraction pattern selected fromthe strong and very strong peaks in Table 50.

TABLE 50 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 4.50 19.6 w 13 5.25 16.8 w 96.04 14.6 w 12 7.40 11.9 m 21 8.80 10.0 w 14 10.66 8.3 m 18 12.13 7.3 m17 13.25 6.7 m 25 14.84 5.97 m 17 16.11 5.50 m 25 17.17 5.16 m 26 17.645.02 vs 100 18.29 4.85 m 26 18.45 4.80 s 38 20.10 4.42 s 49 21.10 4.21 s40 21.53 4.12 s 40 23.26 3.82 s 44 24.36 3.65 m 25 24.68 3.60 m 30 25.183.53 m 24 26.94 3.31 m 16 28.04 3.18 m 19 28.82 3.10 m 17

In some embodiments, Form FUM-P4 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 51.In some embodiments, Form FUM-P4 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,or at least seven peaks in its X-ray powder diffraction pattern selectedfrom those in Table 51.

TABLE 51 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 17.64 5.02 vs 100 18.45 4.80 s38 20.10 4.42 s 49 21.10 4.21 s 40 21.53 4.12 s 40 23.26 3.82 s 44 24.683.60 m 30

In some embodiments, Form FUM-P4 is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 46. In someembodiments, Form FUM-P4 is characterized by one or more peaks in itsRaman spectrum selected from those in Table 52. In some embodiments,Form FUM-P4 is characterized by having a Raman spectrum withcharacteristic peaks at about those in Table 52.

TABLE 52 Raman spectrum. Wavenumber Absolute Normalized (cm⁻¹) IntensityIntensity (%) 3073 0.607 25.9 3049 0.617 26.3 3021 0.478 20.4 2993 0.74531.8 2966 1.052 44.8 2948 0.926 39.5 2917 0.930 39.6 2875 0.743 31.72851 0.541 23.1 1714 0.448 19.1 1663 0.465 19.8 1628 1.482 63.2 16092.346 100.0 1597 1.374 58.6 1502 0.821 35.0 1486 0.529 22.5 1447 0.80434.3 1428 0.785 33.5 1393 0.736 31.4 1351 0.825 35.2 1317 0.303 12.91307 0.328 14.0 1285 0.361 15.4 1272 0.402 17.1 1245 0.383 16.3 12270.434 18.5 1209 0.396 16.9 1147 0.219 9.3 1135 0.254 10.8 1114 0.195 8.31059 0.273 11.6 1027 0.565 24.1 1020 0.559 23.8 1010 0.405 17.3 9920.361 15.4 953 0.156 6.6 914 0.286 12.2 850 0.493 21.0 820 0.205 8.7 7890.815 34.7 741 0.800 34.1 712 0.357 15.2 682 0.319 13.6 604 0.174 7.4585 0.178 7.6 544 0.151 6.4 489 0.207 8.8 470 0.226 9.6 441 0.218 9.3421 0.225 9.6 411 0.216 9.2 399 0.213 9.1 322 0.247 10.5 266 0.346 14.7231 0.358 15.3 207 0.344 14.7 187 0.532 22.7

In some embodiments, Form FUM-P4 is characterized by one or more peaksin its Raman spectrum selected from those in Table 53. In someembodiments, Form FUM-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, or at least ten peaks in its Ramanspectrum selected from those in Table 53.

TABLE 53 Raman spectrum. Wavenumber Absolute Normalized (cm⁻¹) IntensityIntensity (%) 1628 1.482 63.2 1609 2.346 100.0 1597 1.374 58.6 15020.821 35.0 1447 0.804 34.3 1428 0.785 33.5 1393 0.736 31.4 1351 0.82535.2 789 0.815 34.7 741 0.800 34.1

In some embodiments, Form FUM-P4 is characterized by a TG-FTIRthermogram substantially similar to the one depicted in FIG. 47.

In some embodiments, Form FUM-P4 is a solvate. In some embodiments, FormFUM-P4 is a non-stoichiometric solvate. In some embodiments, Form FUM-P4is obtained from tetrahydrofuran. In some embodiments, Form FUM-P4 is atetrahydrofuran solvate.

Malate Salt, Co-Crystal, and Form MLA-P3

The invention also provides a malate (e.g., L-malate and D-malate) saltform of compound 1. The malate salt may be amorphous or exist in one ormore crystalline forms. In certain embodiments, the present inventionprovides crystalline Form MLA-P3 (Form MLA-P3) of compound 1. In someembodiments, Form MLA-P3 is a salt of compound 1. In some embodiments,Form MLA-P3 is an L-malate salt of compound 1. In some embodiments, FormMLA-P3 is a mono-L-malate salt of compound 1. In some embodiments, FormMLA-P3 is a co-crystal of compound 1 and L-malic acid.

In certain embodiments, Form MLA-P3 is substantially free of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form MLA-P3 is 99% flee of impurities by weight. Incertain embodiments, Form MLA-P3 is 97% free of impurities by weight. Incertain embodiments, Form MLA-P3 is 95% free of impurities by weight. Incertain embodiments, Form MLA-P3 is substantially free of amorphousL-malic acid salt of compound 1. In certain embodiments, Form MLA-P3 issubstantially free of other crystalline forms of compound 1.

Form MLA-P3 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form MLA-P3 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 48. In some embodiments, Form MLA-P3is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from those in Table 54. In someembodiments, Form MLA-P3 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, at least twenty-seven, at least twenty-eight, at leasttwenty-nine, at least thirty, at least thirty-one, at least thirty-two,or at least thirty-three peaks in its X-ray powder diffraction patternselected from those in Table 54. In some embodiments, Form MLA-P3 ofcompound 1 is characterized in that it has one or more peaks in itsX-ray powder diffraction pattern selected from the strong and verystrong peaks in Table 54.

TABLE 54 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 4.35 20.3 m 22 4.97 17.8 s 356.72 13.1 s 62 7.83 11.3 vs 82 8.48 10.4 s 36 8.75 10.1 s 61 9.89 8.9 m28 10.64 8.3 m 22 11.35 7.8 w 11 11.86 7.5 w 15 12.52 7.1 s 39 13.15 6.7m 23 13.44 6.6 s 37 14.84 5.97 vs 100 16.75 5.29 s 65 16.93 5.23 s 5917.26 5.13 s 54 17.59 5.04 s 61 18.02 4.92 m 16 19.11 4.64 s 40 19.804.48 s 48 20.93 4.24 s 34 21.96 4.05 s 36 22.32 3.98 s 35 22.78 3.90 s44 23.27 3.82 m 29 24.14 3.68 s 35 24.81 3.59 m 18 25.49 3.49 m 25 27.113.29 m 27 28.37 3.14 w 15 30.38 2.94 m 17 31.38 2.85 m 17

In some embodiments, Form MLA-P3 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 55.In some embodiments, Form MLA-P3 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, or at least nine peaks in its X-raypowder diffraction pattern selected from those in Table 55.

TABLE 55 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 6.72 13.1 s 62 7.83 11.3 vs 828.75 10.1 s 61 14.84 5.97 vs 100 16.75 5.29 s 65 16.93 5.23 s 59 17.265.13 s 54 17.59 5.04 s 61 19.80 4.48 s 48

In some embodiments, Form MLA-P3 is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 49. In someembodiments, Form MLA-P3 is characterized by one or more peaks in itsRaman spectrum selected from those in Table 56. In some embodiments,Form MLA-P3 is characterized by having a Raman spectrum withcharacteristic peaks at about those in Table 56.

TABLE 56 Raman spectrum. Wavenumber Absolute Normalized (cm⁻¹) IntensityIntensity (%) 3337 0.023 4.8 3074 0.095 19.7 3041 0.174 36.1 2992 0.11724.3 2964 0.247 51.2 2948 0.245 50.8 2929 0.382 79.3 2873 0.138 28.61628 0.202 41.9 1601 0.482 100.0 1565 0.176 36.5 1502 0.208 43.2 14490.170 35.3 1430 0.185 38.4 1392 0.177 36.7 1353 0.142 29.5 1344 0.14730.5 1324 0.090 18.7 1299 0.088 18.3 1280 0.109 22.6 1247 0.066 13.71210 0.103 21.4 1165 0.044 9.1 1119 0.042 8.7 1089 0.054 11.2 1062 0.06914.3 1036 0.120 24.9 1028 0.237 49.2 998 0.110 22.8 944 0.038 7.9 9150.043 8.9 854 0.094 19.5 839 0.046 9.5 808 0.236 49.0 791 0.252 52.3 7390.100 20.7 720 0.162 33.6 681 0.096 19.9 578 0.077 16.0 550 0.064 13.3480 0.068 14.1 466 0.058 12.0 441 0.054 11.2 409 0.057 11.8 393 0.05912.2 363 0.042 8.7 331 0.067 13.9 301 0.043 8.9 257 0.102 21.2 226 0.09920.5 196 0.154 32.0 155 0.143 29.7

In some embodiments, Form MLA-P3 is characterized by one or more peaksin its Raman spectrum selected from those in Table 57. In someembodiments, Form MLA-P3 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, orat least twelve peaks in its Raman spectrum selected from those in Table57.

TABLE 57 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 1628 0.202 41.9 1601 0.482 100.0 1565 0.176 36.5 15020.208 43.2 1449 0.170 35.3 1430 0.185 38.4 1392 0.177 36.7 1344 0.14730.5 1028 0.237 49.2 808 0.236 49.0 791 0.252 52.3 720 0.162 33.6

In some embodiments, Form MLA-P3 has a DSC thermogram substantiallysimilar to the one depicted in FIG. 50. In some embodiments, Form MLA-P3has a DSC thermogram with an endotherm having a peak temperature(T_(max)) of about 212° C. In some embodiments, Form MLA-P3 has a DSCthermogram with a ΔH of about 94 J/g.

In some embodiments, Form MLA-P3 is substantially anhydrous. In someembodiments, Form MLA-P3 is obtained from acetone.

Form MLA-P4

In certain embodiments, the present invention provides crystalline FormMLA-P4 (Form MLA-P4) of compound 1. In some embodiments, Form MLA-P4 isa salt of compound 1. In some embodiments, Form MLA-P4 is an L-malatesalt of compound 1. In some embodiments, Form MLA-P4 is a mono-L-malatesalt of compound 1. In some embodiments, Form MLA-P4 is a co-crystal ofcompound 1 and L-malic acid.

In certain embodiments, Form MLA-P4 is substantially fee of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form MLA-P4 is 99% free of impurities by weight. Incertain embodiments, Form MLA-P4 is 97% free of impurities by weight. Incertain embodiments, Form MLA-P4 is 95% free of impurities by weight. Incertain embodiments, Form MLA-P4 is substantially free of amorphousL-malic acid salt of compound 1. In certain embodiments, Form MLA-P4 issubstantially free of other crystalline forms of compound 1.

Form MLA-P4 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form MLA-P4 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 51. In some embodiments, Form MLA-P4is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from those in Table 58. In someembodiments, Form MLA-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, at least twenty-seven, at least twenty-eight, or at leasttwenty-nine peaks in its X-ray powder diffraction pattern selected fromthose in Table 58. In some embodiments, Form MLA-P4 of compound 1 ischaracterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 58.

TABLE 58 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 3.78 23.4 vs 100 5.33 16.6 vs75 6.03 14.6 w 14 7.52 11.7 vs 70 8.40 10.5 s 56 10.39 8.5 m 24 11.897.4 m 24 12.99 6.8 m 22 13.54 6.5 m 30 14.25 6.2 m 27 15.03 5.89 m 2615.53 5.70 s 31 15.94 5.56 s 49 16.81 5.27 s 50 17.44 5.08 s 36 17.774.99 m 23 18.81 4.71 s 52 19.80 4.48 s 32 20.42 4.35 s 31 21.19 4.19 s58 22.09 4.02 s 39 22.63 3.93 s 46 23.71 3.75 s 32 24.24 3.67 s 44 25.403.50 m 30 26.56 3.35 m 24 26.77 3.33 m 21 28.33 3.15 m 25 31.26 2.86 m20

In some embodiments, Form MLA-P4 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 59.In some embodiments, Form MLA-P4 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, or at least eight peaks in its X-ray powder diffiactionpattern selected from those in Table 59.

TABLE 59 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 5.33 16.6 vs 75 7.52 11.7 vs70 8.40 10.5 s 56 16.81 5.27 s 50 18.81 4.71 s 52 21.19 4.19 s 58 22.633.93 s 46 24.24 3.67 s 44

In some embodiments, Form MLA-P4 is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 52. In someembodiments, Form MLA-P4 is characterized by one or more peaks in itsRaman spectrum selected from those in Table 60. In some embodiments,Form MLA-P4 is characterized by having a Raman spectrum withcharacteristic peaks at about those in Table 60.

TABLE 60 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 3345 0.015 3.9 3073 0.063 16.5 3038 0.093 24.4 2967 0.14738.6 2930 0.237 62.2 2873 0.107 28.1 1723 0.029 7.6 1627 0.115 30.2 16060.381 100.0 1566 0.188 49.3 1504 0.160 42.0 1448 0.145 38.1 1433 0.16443.0 1392 0.148 38.8 1357 0.130 34.1 1325 0.069 18.1 1300 0.059 15.51274 0.082 21.5 1246 0.066 17.3 1228 0.058 15.2 1209 0.082 21.5 11290.042 11.0 1091 0.052 13.6 1063 0.057 15.0 1028 0.164 43.0 1000 0.07319.2 953 0.040 10.5 853 0.064 16.8 808 0.145 38.1 792 0.209 54.9 7410.115 30.2 721 0.112 29.4 679 0.075 19.7 579 0.054 14.2 551 0.061 16.0485 0.046 12.1 466 0.053 13.9 442 0.048 12.6 410 0.056 14.7 364 0.04110.8 334 0.059 15.5 262 0.085 22.3 228 0.078 20.5 203 0.123 32.3 1320.248 65.1

In some embodiments, Form MLA-P4 is characterized by one or more peaksin its Raman spectrum selected from those in Table 61. In someembodiments, Form MLA-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, orat least twelve peaks in its Raman spectrum selected from those in Table61.

TABLE 61 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 1627 0.115 30.2 1606 0.381 100.0 1566 0.188 49.3 15040.160 42.0 1448 0.145 38.1 1433 0.164 43.0 1392 0.148 38.8 1357 0.13034.1 1028 0.164 43.0 808 0.145 38.1 792 0.209 54.9 741 0.115 30.2

In some embodiments, Form MLA-P4 has a DSC thermogram substantiallysimilar to the one depicted in FIG. 53.

In some embodiments, Form MLA-P4 has a DVS isotherm substantiallysimilar to the one depicted in FIG. 54.

In some embodiments, Form MLA-P4 has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 55.

In some embodiments, Form MLA-P4 is substantially anhydrous. In someembodiments, Form MLA-P4 is obtained from crystallization fromacetonitrile.

Succinate Salt, Co-Crystal, and Form SUC-P3

The invention also provides a succinate salt form of compound 1. Thesuccinate salt may be amorphous or exist in one or more crystallineforms. In certain embodiments, the present invention providescrystalline Form SUC-P3 (Form SUC-P3) of compound 1. In someembodiments, Form SUC-P3 is a salt of compound 1. In some embodiments,Form SUC-P3 is a succinate salt of compound 1. In some embodiments, FormSUC-P3 is a mono-succinate salt of compound 1. In some embodiments, FormSUC-P3 is a co-crystal of compound 1 and succinic acid.

In certain embodiments, Form SUC-P3 is substantially free of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form SUC-P3 is 99% free of impurities by weight. Incertain embodiments, Form SUC-P3 is 97% free of impurities by weight. Incertain embodiments, Form SUC-P3 is 95% free of impurities by weight. Incertain embodiments, Form SUC-P3 is substantially free of amorphoussuccinic acid salt of compound 1. In certain embodiments, Form SUC-P3 issubstantially free of other crystalline forms of compound 1.

Form SUC-P3 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form SUC-P3 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 56. In some embodiments, Form SUC-P3is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from those in Table 62. In someembodiments, Form SUC-P3 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, at least twenty-seven, or at least twenty-eight peaks in itsX-ray powder diffraction pattern selected from those in Table 62. Insome embodiments, Form SUC-P3 of compound 1 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom the strong and very strong peaks in Table 62.

TABLE 62 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 4.98 17.7 m 22 6.73 13.1 s 507.82 11.3 vs 100 8.75 10.1 s 61 9.87 9.0 s 33 10.64 8.3 m 19 11.85 7.5 m19 12.51 7.1 s 37 13.45 6.6 s 39 14.79 5.98 vs 99 16.81 5.27 s 63 17.255.14 s 46 17.58 5.04 s 57 19.10 4.64 s 37 19.76 4.49 s 53 20.98 4.23 s38 21.56 4.12 s 36 21.95 4.05 s 40 22.46 3.96 s 44 22.82 3.89 s 51 23.373.80 s 38 24.30 3.66 s 36 24.87 3.58 m 21 25.57 3.48 m 29 27.19 3.28 s33 30.44 2.93 m 19 31.37 2.85 m 17 34.90 2.57 m 16

In some embodiments, Form SUC-P3 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 63.In some embodiments, Form SUC-P3 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, or at least eight peaks in its X-ray powder diffractionpattern selected from those in Table 63.

TABLE 63 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 6.73 13.1 s 50 7.82 11.3 vs100 8.75 10.1 s 61 14.79 5.98 vs 99 16.81 5.27 s 63 17.58 5.04 s 5719.76 4.49 s 53 22.82 3.89 s 51

In some embodiments, Form SUC-P3 is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 57. In someembodiments, Form SUC-P3 is characterized by one or more peaks in itsRaman spectrum selected from those in Table 64. In some embodiments,Form SUC-P3 is characterized by having a Raman spectrum withcharacteristic peaks at about those in Table 64.

TABLE 64 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 3340 0.016 4.0 3075 0.076 18.9 3041 0.151 37.6 2964 0.20952.0 2948 0.215 53.5 2930 0.346 86.1 2874 0.122 30.3 2720 0.026 6.5 16280.168 41.8 1601 0.402 100.0 1567 0.175 43.5 1502 0.171 42.5 1449 0.13934.6 1429 0.154 38.3 1392 0.133 33.1 1353 0.122 30.3 1323 0.074 18.41299 0.072 17.9 1280 0.087 21.6 1246 0.051 12.7 1209 0.083 20.6 11660.034 8.5 1120 0.036 9.0 1089 0.044 10.9 1062 0.055 13.7 1028 0.192 47.8997 0.083 20.6 915 0.036 9.0 854 0.079 19.7 839 0.037 9.2 808 0.186 46.3791 0.204 50.7 749 0.052 12.9 739 0.083 20.6 720 0.134 33.3 681 0.07819.4 641 0.025 6.2 577 0.065 16.2 552 0.047 11.7 480 0.059 14.7 4670.047 11.7 441 0.045 11.2 410 0.053 13.2 394 0.061 15.2 361 0.037 9.2332 0.058 14.4 301 0.036 9.0 257 0.085 21.1 225 0.086 21.4 196 0.14335.6 154 0.129 32.1

In some embodiments, Form SUC-P3 is characterized by one or more peaksin its Raman spectrum selected from those in Table 65. In someembodiments, Form SUC-P3 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, orat least twelve peaks in its Raman spectrum selected from those in Table65.

TABLE 65 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 1628 0.168 41.8 1601 0.402 100.0 1567 0.175 43.5 15020.171 42.5 1449 0.139 34.6 1429 0.154 38.3 1392 0.133 33.1 1353 0.12230.3 1028 0.192 47.8 808 0.186 46.3 791 0.204 50.7 720 0.134 33.3

In some embodiments, Form SUC-P3 has a DSC thermogram substantiallysimilar to the one depicted in FIG. 58. In some embodiments, Form SUC-P3has a DSC thermogram with an endotherm having a peak temperature(T_(max)) of about 219° C. In some embodiments, Form SUC-P3 has a DSCthermogram with a ΔH of about 103 J/g.

In some embodiments, Form SUC-P3 has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 59.

In some embodiments, Form SUC-P3 is substantially anhydrous. In someembodiments, Form SUC-P3 is obtained from recrystallization fromacetone.

Form SUC-P4

In certain embodiments, the present invention provides crystalline FormSUC-P4 (SUC-P4) of compound 1. In some embodiments, Form SUC-P4 is asalt of compound 1. In some embodiments, Form SUC-P4 is a succinate saltof compound 1. In some embodiments, Form SUC-P4 is a non-stoichiometricsuccinate salt of compound 1. In some embodiments, Form SUC-P4 is ahemisuccinate salt of compound 1. In some embodiments, Form SUC-P4 is aco-crystal of compound 1 and succinic acid.

In certain embodiments, Form SUC-P4 is substantially free of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form SUC-P4 is 99% free of impurities by weight. Incertain embodiments, Form SUC-P4 is 97% free of impurities by weight. Incertain embodiments, Form SUC-P4 is 95% free of impurities by weight. Incertain embodiments, Form SUC-P4 is substantially free of amorphoussuccinic acid salt of compound 1. In certain embodiments, Form SUC-P4 issubstantially free of other crystalline forms of compound 1.

Form SUC-P4 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form SUC-P4 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 60. In some embodiments, Form SUC-P4is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from those in Table 66. In someembodiments, Form SUC-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, or at least fourteen peaks in its X-raypowder diffraction pattern selected from those in Table 66. In someembodiments, Form SUC-P4 of compound 1 is characterized in that it hasone or more peaks in its X-ray powder diffraction pattern selected fromthe strong and very strong peaks in Table 66.

TABLE 66 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 3.74 23.6 vs 100 5.27 16.7 s44 7.45 11.9 s 60 8.30 10.6 m 18 10.52 8.4 w 11 11.75 7.5 w 13 13.40 6.6w 14 14.86 5.96 w 11 15.77 5.61 m 20 16.63 5.33 m 26 18.60 4.77 m 2018.96 4.68 w 10 21.66 4.10 w 10 22.33 3.98 m 17

In some embodiments, Form SUC-P4 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 67.In some embodiments, Form SUC-P4 is characterized by at least one, atleast two, at least three, at least four, at least five, or at least sixpeaks in its X-ray powder diffraction pattern selected from those inTable 67.

TABLE 67 X-ray powder diffraction pattern. Angle d value Intensity2-Theta ° Angstrom (relative) Intensity % 5.27 16.7 s 44 7.45 11.9 s 608.30 10.6 m 18 15.77 5.61 m 20 16.63 5.33 m 26 18.60 4.77 m 20

In some embodiments, Form SUC-P4 is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 61. In someembodiments, Form SUC-P4 is characterized by one or more peaks in itsRaman spectrum selected from those in Table 68. In some embodiments,Form SUC-P4 is characterized by having a Raman spectrum withcharacteristic peaks at about those in Table 68.

TABLE 68 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 3343 0.022 5.4 3084 0.077 18.9 3037 0.162 39.8 2990 0.14836.4 2975 0.157 38.6 2963 0.193 47.4 2948 0.227 55.8 2930 0.392 96.32874 0.148 36.4 1725 0.027 6.6 1627 0.109 26.8 1601 0.407 100.0 15690.302 74.2 1505 0.167 41.0 1449 0.161 39.6 1428 0.168 41.3 1392 0.14034.4 1383 0.132 32.4 1356 0.120 29.5 1345 0.105 25.8 1323 0.075 18.41299 0.080 19.7 1280 0.096 23.6 1246 0.063 15.5 1209 0.087 21.4 11600.033 8.1 1128 0.044 10.8 1091 0.053 13.0 1063 0.068 16.7 1038 0.10926.8 1028 0.234 57.5 1002 0.089 21.9 930 0.039 9.6 855 0.083 20.4 8070.221 54.3 792 0.245 60.2 740 0.096 23.6 720 0.162 39.8 680 0.096 23.6577 0.074 18.2 551 0.068 16.7 481 0.055 13.5 466 0.054 13.3 442 0.05012.3 409 0.065 16.0 394 0.063 15.5 362 0.043 10.6 333 0.065 16.0 3020.035 8.6 260 0.096 23.6 224 0.083 20.4 200 0.139 34.2 155 0.180 44.2

In some embodiments, Form SUC-P4 is characterized by one or more peaksin its Raman spectrum selected from those in Table 69. In someembodiments, Form SUC-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, or at least elevenpeaks in its Raman spectrum selected from those in Table 69.

TABLE 69 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 1601 0.407 100.0 1569 0.302 74.2 1505 0.167 41.0 14490.161 39.6 1428 0.168 41.3 1392 0.140 34.4 1383 0.132 32.4 1028 0.23457.5 807 0.221 54.3 792 0.245 60.2 720 0.162 39.8

In some embodiments, Form SUC-P4 has a DSC thermogram substantiallysimilar to the one depicted in FIG. 62. In some embodiments, Form SUC-P4has a DSC thermogram with an endotherm having a peak temperature(T_(max)) of about 169° C., about 212° C., or about 215° C. In someembodiments, Form SUC-P4 has a DSC thermogram with a ΔH of about 6.7 J/gor about 92.6 J/g.

In some embodiments, Form SUC-P4 has a DVS isotherm substantiallysimilar to the one depicted in FIG. 63.

In some embodiments, Form SUC-P4 has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 64.

In some embodiments, Form SUC-P4 is substantially anhydrous. In someembodiments, Form SUC-P4 is obtained from recrystallization fromacetonitrile.

Form SUC-P5

In certain embodiments, the present invention provides crystalline FormSUC-P5 (SUC-P5) of compound 1. In some embodiments, Form SUC-P5 is asalt of compound 1. In some embodiments, Form SUC-P5 is a succinate saltof compound 1. In some embodiments, Form SUC-P5 is a non-stoichiometricsuccinate salt of compound 1. In some embodiments, Form SUC-P5 is ahemisuccinate salt of compound 1. In some embodiments, Form SUC-P5 is aco-crystal of compound 1 and succinic acid.

In certain embodiments, Form SUC-P5 is substantially free of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form SUC-P5 is 99% free of impurities by weight. Incertain embodiments, Form SUC-P5 is 97% free of impurities by weight. Incertain embodiments, Form SUC-P5 is 95% free of impurities by weight. Incertain embodiments, Form SUC-P5 is substantially free of amorphoussuccinic acid salt of compound 1. In certain embodiments, Form SUC-P5 issubstantially free of other crystalline forms of compound 1.

Form SUC-P5 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, DSC thermogram, TGA thermogram, solubility, and stability.In some embodiments, Form SUC-P5 is characterized by an X-ray powderdiffraction pattern substantially similar to the one depicted in FIG.87. In some embodiments, Form SUC-P5 is characterized in that it has oneor more peaks in its X-ray powder diffraction pattern selected fromthose in Table 76. In some embodiments, Form SUC-P5 is characterized byat least one, at least two, at least three, at least four, at leastfive, at least six, at least seven, at least eight or at least ninepeaks in its X-ray powder diffraction pattern selected from those inTable 76. In some embodiments, Form SUC-P5 of compound 1 ischaracterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 76.

TABLE 76 X-ray powder diffraction pattern. Angle 2-Theta ° 7.4 8.3 10.511.7 13.2 15.6 16.5 18.5 22.2

In some embodiments, Form SUC-P5 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 77.In some embodiments, Form SUC-P5 is characterized by at least one, atleast two, at least three or at least four peaks in its X-ray powderdiffraction pattern selected from those in Table 77.

TABLE 77 X-ray powder diffraction pattern. Angle 2-Theta ° 7.4 15.6 16.518.5 22.2

In some embodiments, Form SUC-P5 has a DSC thermogram substantiallysimilar to the one depicted in FIG. 88. In some embodiments, Form SUC-P5has a DSC thermogram with an endotherm peak temperature of 207-208° C.In some embodiments, Form SUC-P5 has a DSC thermogram with an endothermpeak temperature of 207-208° C., with an approximately 7-8% weight lossup to that point.

In some embodiments, SUC-P5 is stable for at least about 1 month, atleast about 2 months, at least about 4 months, at least about 6 monthsat about 40° C. and about 75% relative humidity. In some embodiments,SUC-P5 has substantially the same XRPD pattern post storage for at leastabout 1 month, at least about 2 months, at least about 4 months, atleast about 6 months at about 40° C. and about 75% relative humidity. Insome embodiments, SUC-P5 has substantially the same endothermic eventwith a peak at about T_(max)=205-210° C. in DSC of post storage for atleast about 1 month, at least about 2 months, at least about 4 months,at least about 6 months at about 40° C. and about 75% relative humidity.In some embodiments, SUC-P5 is stable for at least about 1 month, atleast about 2 months, at least about 4 months, at least about 6 months,at least about 12 months, at least about 18 months, at least about 2years, or at least about 3 years at about 25° C. and about 60% relativehumidity.

Maleate Salt, Co-Crystals, and Form MLE-P4

The invention also provides a maleate salt form of compound 1. Themaleate salt may be amorphous or exist in one or more crystalline forms.In certain embodiments, the present invention provides crystalline FormMLE-P4 (Form MLE-P4) of compound 1. In some embodiments, Form MLE-P4 isa salt of compound 1. In some embodiments, Form MLE-P4 is a maleate saltof compound 1. In some embodiments, Form MLE-P4 is a non-stoichiometricmaleate salt of compound 1. In some embodiments, Form MLE-P4 is aco-crystal of compound 1 and maleic acid.

In certain embodiments, Form MLE-P4 is substantially free of impurities.In certain embodiments, the impurity is compound 1 in free base form. Incertain embodiments, Form MLE-P4 is 99% free of impurities by weight. Incertain embodiments, Form MLE-P4 is 97% free of impurities by weight. Incertain embodiments, Form MLE-P4 is 95% free of impurities by weight. Incertain embodiments, Form MLE-P4 is substantially free of amorphousmaleic acid salt of compound 1. In certain embodiments, Form MLE-P4 issubstantially free of other crystalline forms of compound 1.

Form MLE-P4 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form MLE-P4 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 65. In some embodiments, Form MLE-P4is characterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from those in Table 70. In someembodiments, Form MLE-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, at least twenty-seven, at least twenty-eight, at leasttwenty-nine, at least thirty, at least thirty-one, at least thirty-two,at least thirty-three, at least thirty-four, at least thirty-five, atleast thirty-six, at least thirty-seven, at least thirty-eight, at leastthirty-nine, at least forty, at least forty-one, or at least forty-twopeaks in its X-ray powder diffraction pattern selected from those inTable 70. In some embodiments, Form MLE-P4 of compound 1 ischaracterized in that it has one or more peaks in its X-ray powderdiffraction pattern selected from the strong and very strong peaks inTable 70.

TABLE 70 X-ray powder diffraction pattern. Angle d value IntensityIntensity 2-Theta ° Angstrom (relative) % 6.09 14.5 m 26 7.51 11.8 w 78.63 10.2 s 40 10.67 8.3 s 47 12.16 7.3 w 9 12.57 7.0 m 18 13.01 6.8 s58 15.01 5.90 s 41 16.02 5.53 w 10 16.32 5.43 s 53 17.04 5.20 m 25 17.295.12 vs 100 17.53 5.06 m 22 17.93 4.94 w 11 18.31 4.84 s 36 18.73 4.73 m25 19.78 4.49 s 67 20.56 4.32 m 22 20.91 4.24 s 68 21.42 4.14 m 28 21.924.05 m 17 22.48 3.95 s 55 22.95 3.87 w 14 23.11 3.85 w 11 23.68 3.75 m27 24.31 3.66 s 39 24.81 3.59 w 14 25.29 3.52 s 30 25.71 3.46 w 14 26.123.41 m 18 26.47 3.36 w 11 26.83 3.32 m 30 27.36 3.26 w 12 27.99 3.19 s34 28.39 3.14 s 42 28.64 3.11 m 15 30.40 2.94 m 18 30.70 2.91 w 13 31.112.87 m 20 32.97 2.71 w 12 33.42 2.68 w 10 34.98 2.56 w 11

In some embodiments, Form MLE-P4 is characterized by one or more peaksin its X-ray powder diffraction pattern selected from those in Table 71.In some embodiments, Form MLE-P4 is characterized by at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, at least nine, at least ten, at leasteleven, or at least twelve peaks in its X-ray powder diffraction patternselected from those in Table 71.

TABLE 71 X-ray powder diffraction pattern. Angle d value IntensityIntensity 2-Theta ° Angstrom (relative) % 8.63 10.2 s 40 10.67 8.3 s 4713.01 6.8 s 58 15.01 5.90 s 41 16.32 5.43 s 53 17.29 5.12 vs 100 18.314.84 s 36 19.78 4.49 s 67 20.91 4.24 s 68 22.48 3.95 s 55 24.31 3.66 s39 28.39 3.14 s 42

In some embodiments, Form MLE-P4 is characterized by a Raman spectrumsubstantially similar to the one depicted in FIG. 66. In someembodiments, Form MLE-P4 is characterized by one or more peaks in itsRaman spectrum selected from those in Table 72. In some embodiments,Form MLE-P4 is characterized by having a Raman spectrum withcharacteristic peaks at about those in Table 72.

TABLE 72 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 3383 0.019 3.2 3071 0.174 29.0 3060 0.229 38.1 3023 0.15826.3 3007 0.126 21.0 2971 0.270 44.9 2947 0.153 25.5 2924 0.233 38.82870 0.156 26.0 2838 0.111 18.5 1750 0.206 34.3 1722 0.097 16.1 17000.174 29.0 1652 0.261 43.4 1629 0.531 88.4 1611 0.601 100.0 1594 0.37862.9 1569 0.213 35.4 1503 0.327 54.4 1487 0.171 28.5 1462 0.112 18.61447 0.249 41.4 1432 0.306 50.9 1392 0.231 38.4 1358 0.283 47.1 13310.163 27.1 1321 0.130 21.6 1307 0.096 16.0 1287 0.098 16.3 1271 0.14023.3 1258 0.103 17.1 1247 0.125 20.8 1222 0.158 26.3 1209 0.139 23.11148 0.076 12.6 1134 0.087 14.5 1115 0.075 12.5 1093 0.081 13.5 10590.099 16.5 1040 0.088 14.6 1027 0.170 28.3 1018 0.170 28.3 998 0.11118.5 991 0.111 18.5 951 0.073 12.1 863 0.279 46.4 854 0.213 35.4 8190.068 11.3 785 0.265 44.1 741 0.264 43.9 712 0.096 16.0 682 0.116 19.3602 0.101 16.8 585 0.074 12.3 548 0.067 11.1 485 0.099 16.5 442 0.07712.8 403 0.101 16.8 374 0.076 12.6 310 0.163 27.1 266 0.130 21.6 2330.129 21.5 185 0.199 33.1 140 0.577 96.0 110 0.589 98.0

In some embodiments, Form MLE-P4 is characterized by one or more peaksin its Raman spectrum selected from those in Table 73. In someembodiments, Form MLE-P4 is characterized by at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, or at least elevenpeaks in its Raman spectrum selected from those in Table 73.

TABLE 73 Raman spectrum. Wavenumber Normalized Intensity (cm⁻¹) AbsoluteIntensity (%) 1652 0.261 43.4 1629 0.531 88.4 1611 0.601 100.0 15940.378 62.9 1503 0.327 54.4 1447 0.249 41.4 1432 0.306 50.9 1358 0.28347.1 863 0.279 46.4 785 0.265 44.1 741 0.264 43.9

In some embodiments, Form MLE-P4 has a DSC thermogram substantiallysimilar to the one depicted in FIG. 67. In some embodiments, Form MLE-P4has a DSC thermogram with an endotherm having a peak temperature(T_(max)) of about 112.8° C. or about 139.9° C. In some embodiments,Form MLE-P4 has a DSC thermogram with a ΔH of about 55.5 J/g or about51.3 J/g)

In some embodiments, Form MLE-P4 has a TG-FTIR thermogram substantiallysimilar to the one depicted in FIG. 68.

In certain embodiments, Form MLE-P4 has a melting point of about140-150° C. In some embodiments, Form MLE-P4 is substantially anhydrous.In some embodiments, Form MLE-P4 is obtained from recrystallization fromacetone.

Form MLE-P6

In certain embodiments, the present invention provides crystalline FormMLE-P6 of compound 1. In some embodiments, Form MLE-P6 is a salt ofcompound 1. In some embodiments, Form MLE-P6 is a maleate salt ofcompound 1. In some embodiments, Form MLE-P6 is a non-stoichiometricmaleate salt of compound 1. In some embodiments, Form MLE-P6 is aco-crystal of compound 1 and maleic acid

In certain embodiments, Form MLE-P6 is substantially free of impurities.In certain embodiments, Form MLE-P6 is 99% free of impurities by weight.In certain embodiments, Form MLE-P6 is 97% free of impurities by weight.In certain embodiments, Form MLE-P6 is 95% free of impurities by weight.In certain embodiments, Form MLE-P6 is substantially free of amorphouscompound 1. In certain embodiments, Form MLE-P6 is substantially free ofother crystalline forms of compound 1.

Form MLE-P6 can be characterized by one or more of the characteristicsdescribed herein including, but not limited to, XRPD diffraction patternand/or peaks, Raman spectrum and/or peaks, DSC thermogram, DVS isotherm,TG-FTIR thermogram, IR spectrum and/or peaks, appearance, melting point,solubility, and stability. In some embodiments, Form MLE-P6 ischaracterized by an X-ray powder diffraction pattern substantiallysimilar to the one depicted in FIG. 84.

In some embodiments, Form MLE-P6 is substantially anhydrous. In someembodiments, Form MLE-P6 is obtained from recrystallization fromacetone.

Pharmaceutical Compositions

In some embodiments, the present invention provides a compositioncomprising a solid or salt form of compound 1 described herein andoptionally a pharmaceutically acceptable excipient. In certainembodiments, the present invention provides a composition comprising afumarate, L-malate, D-malate, succinate, maleate, thiocyanate, oxalate,benzoate, 2-oxoglutarate, or tartrate salt of compound 1 (e.g., a solidform of a fumarate, L-malate, D-malate, succinate, maleate, thiocyanate,oxalate, benzoate, 2-oxoglutarate, or tartrate salt of compound 1described herein) and optionally a pharmaceutically acceptableexcipient. In some embodiments, the amount of compound 1, or a fumarate,L-malate, D-malate, succinate, maleate, thiocyanate, oxalate, benzoate,2-oxoglutarate, or tartrate salt of compound 1, in a compositiondescribed herein is such that it is effective to treat and/or prevent adisease, disorder, or condition. In certain embodiments, a providedcomposition is formulated for administration to a patent in need of suchcomposition. In certain embodiments, a provided composition isformulated for oral administration to a patient. In certain embodiments,a provided composition is formulated into an oral dosage form. Incertain embodiments, a provided composition is formulated into a tablet,powder, pill, capsule, or the like, for oral ingestion by a patient.

Suitable techniques, carriers, and excipients include those foundwithin, for example, Remington: The Science and Practice of Pharmacy,19′^(h) edition, Mack Publishing Company, Easton, Pa. 1995; Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., PharmaceuticalDosage Forms, Marcel Decker, New York, N.Y. 1980; and PharmaceuticalDosage Forms and Drug Delivery Systems, 7^(th) edition, LippincottWilliams & Wilkins, 1999, all of which are incorporated herein byreference in their entireties.

In general, doses of provided pharmaceutical compositions employed foradult human treatment are typically in the range of about 0.01 mg toabout 5000 mg per day. In certain embodiments, doses employed for adulthuman treatment are from about 1 mg to about 1000 mg per day. In certainembodiments, a desired dose is conveniently presented in a single doseor in divided doses administered simultaneously (or over a short periodof time) or at appropriate intervals, for example, as two, three, fouror more sub-doses per day.

It will be understood that a specific dosage and treatment regimen forany particular patient may depend on a variety of factors, including theactivity of the specific compound employed, age, body weight, generalhealth, sex, diet, time of administration, rate of excretion, drugcombination, and the judgment of the treating physician and the severityof the particular disease being treated. The amount of a providedcompound in the composition may also depend upon the particular compoundin the composition.

In some embodiments, a provided pharmaceutical composition comprisesForm C. In some embodiments, a provided pharmaceutical compositioncomprises Form D. In some embodiments, a provided pharmaceuticalcomposition comprises Form E. In some embodiments, a providedpharmaceutical composition comprises Form F. In some embodiments, aprovided pharmaceutical composition comprises Form G. In someembodiments, a provided pharmaceutical composition comprises Form H. Insome embodiments, a provided pharmaceutical composition comprises FormI. In some embodiments, a provided pharmaceutical composition comprisesForm J. In some embodiments, a provided pharmaceutical compositioncomprises Form K. In some embodiments, a provided pharmaceuticalcomposition comprises Form L. In some embodiments, a providedpharmaceutical composition comprises Form M. In some embodiments, aprovided pharmaceutical composition comprises a fumarate salt ofcompound 1. In some embodiments, a provided pharmaceutical compositioncomprises Form FUM-P3. In some embodiments, a provided pharmaceuticalcomposition comprises Form FUM-P4. In some embodiments, a providedpharmaceutical composition comprises an L-malate salt of compound 1. Insome embodiments, a provided pharmaceutical composition comprises aD-malate salt of compound 1. In some embodiments, a providedpharmaceutical composition comprises Form MLA-P3. In some embodiments, aprovided pharmaceutical composition comprises Form MLA-P4. In someembodiments, a provided pharmaceutical composition comprises a succinatesalt of compound 1. In some embodiments, a provided pharmaceuticalcomposition comprises Form SUC-P3. In some embodiments, a providedpharmaceutical composition comprises Form SUC-P4. In some embodiments, aprovided pharmaceutical composition comprises Form SUC-P5. In someembodiments, a provided pharmaceutical composition comprises a maleatesalt of compound 1. In some embodiments, a provided pharmaceuticalcomposition comprises Form MLE-P4. In some embodiments, a providedpharmaceutical composition comprises a maleate salt of compound 1. Insome embodiments, a provided pharmaceutical composition comprises FormMLE-P6. In some embodiments, a provided pharmaceutical compositioncomprises a thiocyanate salt of compound 1. In some embodiments, aprovided pharmaceutical composition comprises an oxalate salt ofcompound 1. In some embodiments, a provided pharmaceutical compositioncomprises a benzoate salt of compound 1. In some embodiments, a providedpharmaceutical composition comprises a 2-oxoglutarate salt ofcompound 1. In some embodiments, a provided pharmaceutical compositioncomprises a tartrate salt of compound 1.

Methods of Treatment, Uses, and Administration

The present disclosure contemplates the treatment or prophylaxis of adisease of the central nervous system, such as mood disorders (e.g.,depression), anxiety disorders, and neurodegenerative diseases. The termneurodegenerative disease encompasses a condition leading to theprogressive loss of the structure or function of neurons, including thedeath of neurons. Examples of neurodegenerative diseases contemplatedherein include, but are not limited to, AIDS dementia complex,adrenoleukodystrophy, alexander disease, Alpers' disease, arnyotrophiclateral sclerosis, ataxia telangiectasia, Batten disease, bovinespongiform encephalopathy, brainstem and cerebellun atrophy, Canavandisease, corticobasal degeneration, Creutzfeldt-Jakob disease, dementiawith Lewy bodies, fatal familial insomnia, Friedrich's ataxia, familialspastic paraparesis, frontotemporal lobar degeneration, Huntington'sdisease, infantile Refsum disease, Kennedy's disease, Krabbe disease,Lyme disease, Machado-Joseph disease, monomelic amyotrophy, multiplesclerosis, multiple system atrophy, neuroacanthocytosis, Niemaum-Pickdisease, neurodegeneration with brain iron accumulation, opsoclonusmyoclonus, Parkinson's disease, Pick's disease, primary lateralsclerosis, progranulin, progressive multifocal leukoencephalopathy,progressive supranuclear palsy, protein aggregation, Refsum disease,Sandhoff disease, diffuse myelinoclastic sclerosis, Shy-Drager syndrome,spinocerebellar ataxia, spinal muscular atrophy, spinal and bulbarmuscular atrophy, subacute combined degeneration of spinal cord, Tabesdorsalis, Tay-Sachs disease, toxic encephalopathy, transmissiblespongiform encephalopathy, and Wobbly hedgehog syndrome.

In certain embodiments, compound 1, and/or one or more salt forms orpolymorphs of compound 1, can be used to treat, ameliorate the signsand/or symptoms of, prevent, or otherwise delay the onset or developmentof the CNS disease, disorder, or condition.

Taught herein, therefore, is the use of compound 1, and/or one or moresalt forms or polymorphs of compound 1 described herein, or apharmaceutically acceptable preparation thereof, in the manufacture of amedicament for treating and/or preventing central nervous systemdisorders, such as mood disorders (e.g., depression), anxiety disorders,or neurodegenerative diseases, in a subject in need thereof.

Also provided herein are methods of treating or preventing centralnervous system disorders, such as mood disorders (e.g., depression),anxiety disorders, or neurodegenerative diseases comprising theadministration of an effective amount of compound 1, and/or one or moresalt forms or polymorphs of compound 1 described herein, or apharmaceutically acceptable preparation thereof, to a subject in needthereof.

As used herein mood disorders are broadly recognized and clearly definedby the relevant DSM-IV-TR (Diagnostic and Statistical Manual of MentalDisorders, 4th Edition, Text Revision) criteria. Thus, there aredepressive disorders of which the best known and most researched ismajor depressive disorder (MDD) commonly called clinical depression ormajor depression, and bipolar disorder (BD), formerly known as manicdepression and characterized by intermittent episodes of mania orhypomania, usually interlaced with depressive episodes. Other depressivedisorders include: atypical depression, melancholic depression,psychotic major depression, catatonic depression, postpartum depression,seasonal affective disorder, dysthymia, depressive disorder nototherwise specified (DD-NOS) (e.g., recurrent brief depression, minordepressive disorder), substance induced mood disorders (e.g., alcoholinduced mood disorders, benzodiazepine induced mood disorders,interferon-alpha induced mood disorders).

Persons of skill in the art will be familiar with the lag period oftraditional antidepressant medications, and with the heightened anxietyproduced by the newer generation antidepressants, including SSRI's,SNRI's and NRI's in the early stages of treatment before theantidepressant effects are seen (within 2-4 weeks). Thus, in certainembodiments, the compounds described herein can be administered to asubject in need thereof as a substitute or replacement for traditionalantidepressant medication. In other embodiments, compounds describedherein can be administered to a subject in need thereof as a supplementto traditional antidepressant medication. In other embodiments, there isprovided a method for treating or preventing depression in a subject,the method including the step of administering to said subject acompound (e.g., an amorphous or crystalline form of compound 1), or anembodiment thereof, described herein, or a salt form or pharmaceuticalcomposition thereof, in the absence of adjunct antidepressant therapy.

Replacing traditional antidepressant medication with the presentcompounds can be advantageous, particularly where the traditionalmedication is associated with one or more adverse effects (e.g.,anxiety, nausea, headaches, erectile dysfunction, early-onset suicidaltendencies, etc). Examples of traditional antidepressant medicationwould be known to those skilled in the art and include, but are notlimited to, selective serotonin re-uptake inhibitors (SSRI),serotonin/noradrenalin re-uptake inhibitors, selective noradrenalinre-uptake inhibitors, monoamine oxidase inhibitors, tricyclicantidepressants, lithium and other mood stabilisers, atypicalantidepressants, and hormones such as estrogen or progestogen.

In other embodiments, the present compounds are administered to asubject in need thereof, together with traditional antidepressants for aperiod of about 2-4 weeks, to address the symptoms of depression, withthe option of discontinuing treatment with the present compounds whilstcontinuing with the traditional therapy. In other embodiments, thesubject is treated with both a present compound and one or moretraditional antidepressant medications (administered sequentially or incombination) for the duration of the treatment period. Such combinationtherapy may be particularly useful, for example, where the combinationof a present compound and one or more traditional antidepressantmedications provides relief from depression in the acute lag phase ofthe treatment period and/or where an additive or synergisticantidepressant therapeutic effect is desired.

Depression relapse can also occur in patients treated with traditionalantidepressant medication. Many such compounds are administered foranywhere from months to years and a reduction in efficacy is often seenwith such long-term use, leading to significant continuing depressionand dysfunction. Depression relapse may be sudden onset for somepatients, while for others it might be evident as a gradual decline inmood and function, which diminishes over time as the patient approachesthe state of relapse. Thus, patients who experience sudden onset ofdepression relapse or a gradual depression relapse would benefit fromthe methods disclosed herein, as the present compound, or salt forms orpolymorphs thereof, can offset the diminishing effect of traditionalantidepressant therapy. Thus, the use of the present compound, or saltforms or polymorphs thereof may prevent or partly alleviate depressionrelapse often seen in patients taking traditional antidepressantmedication.

Thus, in certain embodiments, provided herein are methods for treatingor preventing relapse in a subject receiving antidepressant therapy, themethod including the step of administering to said subject compound 1,or a salt form or polymorph thereof, or a pharmaceutical compositionthereof.

The traditional antidepressant therapies that are associated withpotential depression relapse in a subject would be known to thoseskilled in the art. Examples include, but are not limited to, dosageincreases, alternative SSRIs or SNRIs, and non-SSRI antidepressants suchas noradrenaline re-uptake inhibitors, monoamine oxidase inhibitors,tricyclic antidepressants, lithium and other mood stabilisers, atypicalantidepressants and hormones such as estrogen and progestogen, alsoreferred to herein as “second antidepressant compounds.”

The desired therapeutic activity, or effect, will typically depend onthe condition being treated. For example, where the subject is beingtreated for depression, the therapeutic effect may be a reduction in atleast one clinical symptom of depression, including, but not limited to,cognitive impairment, loss of appetite, mood, and/or inactivity.

In certain embodiments, compound 1, or one or more salt forms orpolymorphs thereof described herein, or a pharmaceutically acceptablepreparation thereof, is administered to said subject sequentially (i.e.,before or after) or in combination with a second antidepressant compound(e.g., with existing antidepressant therapy).

In certain embodiments, the present compound, or salt forms orpolymorphs thereof, have the further added advantage over traditionaltherapy in that they exhibit reduced sedative side effects which mayadversely affect a patient's quality of life. In certain embodiments,the present compound, or salt forms or polymorphs thereof, are free ofmeasurable sedative side effects.

Sudden discontinuation of antidepressant medication may producewithdrawal effects caused by physical dependence on the drug. Compoundscan be evaluated for physical dependence in a simple animal model where,following a period of chronic dosing (e.g., for 14-20 days), the studydrug is stopped and measurements of food intake, body weight, and bodytemperature are taken over the next 5 days. The symptoms of abruptdiscontinuation of the drug are manifest as significantly reducedappetite, weight loss, and drop in body temperature. This model issuitable for detecting the effects across a broad range of drug classesincluding opiates, antidepressants, and benzodiazepines. The compound,or salt forms or polymorphs thereof described herein also can be used asa combination therapy, e.g., combining the treatment with otherantidepressants such as benzodiazepines (e.g., alprazolam, diazepam,lorazepam, clonezepam), selective serotonin re-uptake inhibitors (SSRI)(e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine,indalpine, paroxetine, sertraline, zimelidine, vilaxodone), serotoninnorepinephrine reuptake inhibitors (SNRI) (e.g., venlafaxine,duloxetine, desvenlafaxine, milnacipran), monoamine oxidase inhibitors(e.g., phenelzine, moclobemide), tricyclic antidepressants (e.g.,trimipramine, imipramine), tetracyclic antidepressants (e.g.,mertazepine, maprotiline), mood stabilisers (e.g. lithium, sodiumvalproate, valproic acid), atypical antidepressants (e.g., bupropion),acetylcholinesterase inhibitors (e.g., donepezil, galantamine,rivastigmine), atypical antipsychotics (e.g., risperidone, aripipizole,quetiapine, olanzapine), and hormones such as estrogen and progestogen.

It will thus be understood that compound 1, or salt forms or polymorphsthereof, can be used in the treatment and/or prevention of a disease,such as a disease responsive to or associated with neurite outgrowth. Incertain embodiments, the neurite outgrowth-responsive disease beingtreated and/or prevented using compound 1, or a salt or polymorphthereof, is a neurodegenerative disease. In a certain embodiments, theneurodegenerative disease is multiple sclerosis or a Parkinsonianrelated disorder. In a further embodiment, the neurodegenerative diseaseis multiple sclerosis. In a further embodiment, the disease may involvea condition which involves neural damage including, but not limited to,wound healing, spinal cord injury, and peripheral nerve disorders.

Also contemplated herein is a sub-threshold disease, condition, state,disorder, or trauma. In an embodiment, the disease, condition, state,disorder, or trauma is defined by its symptoms. Hence, compound 1, or asalt form or polymorph thereof contemplated heroin, is useful inameliorating the symptoms of a disease, condition, state, disorder, ortrauma of the CNS. In certain embodiments, the trauma of the CNSincludes stroke, brain hemorrhage, or another condition or event of thesystemic vasculature which affects the CNS. The symptoms of a disease,condition, state, disorder, or trauma of the CNS would be familiar tothose skilled in the art. Examples of such symptoms include mooddisorders, such as depression. Thus, in certain embodiments, thecompound forms described herein are used in the treatment of depressionattributed to (or associated with) a neurodegenerative disease in thesubject.

The compound forms described herein may also be used as therapy, e.g.,combining the treatment with other neurodegenerative treatments, such asacetylcholineesterase inhibitors (e.g., Aricept, Exelon), and treatmentsfor multiple sclerosis (e.g., Avonex, Betaseron, Copaxone, Tysabri,Gilenya).

In a further embodiment there is also provided a method of treatment ofdisorders of the central nervous system comprising the administration ofan effective amount of compound 1, or a salt form or polymorph thereof,to a subject in need thereof.

It will be understood that compound 1, or a salt form or polymorphthereof as described herein, can be used in the treatment of anxiety orconditions/disease states associated with anxiety such as irritablebowel syndrome and fibromyalgia.

In certain embodiments, an anxiety disorder is classified as one of thefollowing:

panic disorder,

obsessive-compulsive disorder (OCD),

post-traumatic stress disorder (PTSD),

social phobia (or social anxiety disorder (SAD),

specific phobias,

generalized anxiety disorder (GAD),

substance-induced anxiety disorder, and

acute stress disorder (ASD).

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of a panic disorder.

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of obsessive-compulsivedisorder (OCD).

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of post-traumaticstress disorder (PTSD).

In an embodiment compound 1, or a salt form or polymorph thereof, asdescribed herein may be used in the treatment of social phobia (orsocial anxiety disorder—SAD).

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of specific phobias. Incertain embodiments, compound 1 or a salt form or polymorph thereof, asdescribed herein may be used for agoraphobia or agoraphobia withouthistory of panic disorder. In certain embodiments, compound 1 or a saltform or polymorph thereof, as described herein may be used for animalphobia.

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of substance-inducedanxiety disorder.

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of acute stressdisorder (ASD).

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of generalized anxietydisorder (GAD).

Generalised anxiety disorder criteria include:

(i) At least 6 months of “excessive anxiety and worry” about a varietyof events and situations. Generally, “excessive” can be interpreted asmore than would be expected for a particular situation or event. Mostpeople become anxious over certain things, but the intensity of theanxiety typically corresponds to the situation.(ii) There is significant difficulty in controlling the anxiety andworry. If someone has a very difficult struggle to regain control,relax, or cope with the anxiety and worry, then this requirement is met.(iii) The presence for most days over the previous six months of 3 ormore (only 1 for children) of the following symptoms:

1. Feeling wound-up, tense, or restless

2. Easily becoming fatigued or worn-out

3. Concentration problems

4. Irritability

5. Significant tension in muscles

6. Difficulty with sleep

(iv) The symptoms are not part of another mental disorder.

(v) The symptoms cause “clinically significant distress” or problemsfunctioning in daily life. “Clinically significant” is the part thatrelies on the perspective of the treatment provider. Some people canhave many of the aforementioned symptoms and cope with them well enoughto maintain a high level of functioning.(vi) The condition is not due to a substance or medical issue.

In certain embodiments, a subject to be treated with compound 1, or asalt form or polymorph thereof, as described herein may be identified byone or more of the above criteria for generalized anxiety disorder.

In certain embodiments, compound 1, or a salt form or polymorph thereof,as described herein may be used to treat or prevent one or more symptomsassociated with an anxiety disorder.

Each anxiety disorder has different symptoms, but all the symptomscluster around excessive, irrational fear and dread.

In another embodiment compound 1, or a salt form or polymorph thereof,as described herein may be used in the treatment of depression, forinstance, major depressive disorder.

Major depressive disorder criteria include:

(i) At least five of the following symptoms have been present during thesame 2-week period and represent a change from previous functioning: atleast one of the symptoms is either

-   -   1) depressed mood, or    -   2) loss of interest or pleasure.        (ii) Depressed mood most of the day, nearly every day, as        indicated either by subjective report (e.g., feels sad or empty)        or observation made by others (e.g., appears tearful).        (iii) Markedly diminished interest or pleasure in all, or almost        all, activities most of the day, nearly every day (as indicated        either by subjective account or observation made by others).        (iv) Significant weight loss when not dieting or weight gain        (e.g., a change of more than 5% of body weight in a month), or        decrease or increase in appetite nearly every day.        (v) Insomnia or hypersomnia nearly every day.        (vi) Psychomotor agitation or retardation nearly every day        (observable by others, not merely subjective feelings of        restlessness or being slowed down).        (vii) Fatigue or loss of energy nearly every day.        (viii) Feelings of worthlessness or excessive or inappropriate        guilt (which may be delusional) nearly every day (not merely        self-reproach or guilt about being sick).        (ix) Diminished ability to think or concentrate, or        indecisiveness, nearly every day (either by subjective account        or as observed by others).        (x) Recurrent thoughts of death (not just fear of dying),        recurrent suicidal ideation without a specific plan, or a        suicide attempt or specific plan for committing suicide        (xi) The symptoms do not meet criteria for a mixed episode.        (xii) The symptoms cause clinically significant distress or        impairment in social, occupational, or other important areas of        functioning.        (xiii) The symptoms are not due to the direct physiological        effects of a substance (e.g. a drug of abuse, a medication) or a        general medical condition (e.g., hypothyroidism).        (xiv) The symptoms are not better accounted for by bereavement,        i.e., after the loss of a loved one, the symptoms persist for        longer than 2 months or are characterized by marked functional        impairment, morbid preoccupation with worthlessness, suicidal        ideation, psychotic symptoms, or psychomotor retardation.

The above criteria have been sourced from the American PsychiatricAssociation (2000) Diagnostic and Statistical Manual of Mental Disorders(4th Ed., Text Revision). Washington D.C.: American PsychiatricAssociation.

In certain embodiments, a subject to be treated with compound 1, or asalt form or polymorph thereof, as described herein may be identified byone or more of the above criteria for major depressive disorder.

In another embodiment compound 1, or a salt form or polymorph thereof,as described herein may be used to treat or prevent one or more symptomsassociated with depression.

Further disorders for which compound 1, or a salt form or polymorphthereof, as described herein may be of benefit include pain andnociception; emesis, including acute, delayed and anticipatory emesis,in particular emesis induced by chemotherapy or radiation, as well asmotion sickness, and post-operative nausea and vomiting; eatingdisorders including anorexia nervosa and bulimia nervosa; premenstrualsyndrome; muscle spasm or spasticity, e.g. in paraplegic patients;hearing disorders, including tinnitus and age-related hearingimpairment; urinary incontinence; and the effects of substance abuse ordependency, including alcohol withdrawal, neuroses, convulsions,migraine, depressive disorder, bipolar disorder, psychotic disorder,neurodegeneration arising from cerebral ischemia, attention deficithyperactivity disorder, Tourette's syndrome, speech disorder, disordersof circadian rhythm, single-episode or recurrent major depressivedisorder, dysthymic disorder, bipolar I or bipolar II manic disorder,cyclothymic disorder, schizophrenia, and stuttering.

In an embodiment compound 1, or a salt form or polymorph thereof, asdescribed herein may be used in the treatment of cerebral ischemia. Incertain embodiments, compound 1, or a salt form or polymorph thereof, asdescribed herein may be used in the treatment of neurodegenerationarising from cerebral ischemia.

In an embodiment compound 1, or a salt form or polymorph thereof, asdescribed herein may be used in the treatment of disorders of thecircadian rhythm.

In an embodiment compound 1, or a salt form or polymorph thereof, asdescribed herein may be used in the treatment of pain and nociception.

In an embodiment compound 1, or a salt form or polymorph thereof, asdescribed herein may be used in the treatment of Alzheimer's disease.

It should be appreciated that compound 1, or a salt form or polymorphthereof, a described herein can be administered to a subject in atreatment effective amount. In some embodiments, a treatment effectiveamount is a therapeutically effective amount or a prophylacticallyeffective amount.

Dosing may occur at intervals of minutes, hours, days, weeks, months oryears or continuously over any one of these periods. Suitable dosageslie within the range of about 0.1 ng per kg of body weight to 1 g per kgof body weight per dosage. The dosage may be in the range of 1 μg to 1 gper kg of body weight per dosage, such as is in the range of 1 mg to 1 gper kg of body weight per dosage. In one embodiment, the dosage may bein the range of 1 mg to 500 mg per kg of body weight per dosage. Inanother embodiment, the dosage may be in the range of 1 mg to 250 mg perkg of body weight per dosage. In yet another embodiment, the dosage maybe in the range of 1 mg to 100 mg per kg of body weight per dosage, suchas up to 50 mg per body weight per dosage.

In certain embodiments, a provided method comprises administering to asubject in need thereof the present compound, or salt form or polymorphthereof, in a dosage to provide an effective amount in vivo that willenhance neurite outgrowth (neurogenesis), including, but not limited tothe acute stages of treatment (e.g., within 1, 2, 3, or 4 weeks from thecommencement of treatment). In an embodiment, an effective amount invivo has an in vitro equivalent concentration that is sufficient toincrease neurite outgrowth by at least 5%, at least 10%, at least 20%,or at least 50% in a neurite outgrowth assay, for example, a neuriteoutgrowth assay described herein. Methods of determining an in vitroequivalent concentration of the present compounds would be familiar tothe skilled artisan. For example, at from about 10 minutes to about 60minutes after administration of the present compounds to a subject, ablood sample is taken and assayed by HPLC, ELISA, gas chromatography, orby other suitable assay to determine the concentration per ml of blood.An equivalent effective concentration can then be used in an in vitroassay once factors such as the weight of the subject, the appropriateblood volume of the subject and the appropriate rate of diffusion of thepresent compound across the blood-brain barrier are taken into account.In another embodiment, when the present compound is found to stimulateneurite outgrowth in vitro (as compared to a control), an approximate invivo effective amount can be determined for a subject by extrapolatingthe in vitro concentration to an in vivo equivalent. Factors such as theweight of the subject, the appropriate blood volume of the subject andthe appropriate rate of diffusion of the present compound across theblood-brain barrier may be used to extrapolate an in vivo effectiveamount and hence the appropriate dosage amount that would give rise tosaid in vivo effective amount.

Thereafter, treatment with the compound 1, or a salt form or polymorphthereof, may be continued throughout the treatment period or it may beceased or replaced with traditional therapeutic compounds. Methods ofdetermining the effective amount of compound 1, or a salt form orpolymorph thereof, that is required for enhancing neurite outgrowth(neurogenesis) in vivo would be familiar to those skilled in the art.For example, enhancement of neurogenesis can be determined by measuringa symptom of the CNS disorder including, but not limited to, cognitiveimpairment, degree and frequency of seizures or tremors,motordysfunction, headaches and mood (e.g., degree of happiness).

In certain embodiments, an effective amount of compound 1, or a saltform or polymorph thereof, for administration one or more times a day toa 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mgto about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of acompound per unit dosage form.

In certain embodiments, compound 1, or a salt form or polymorph thereof,may be at dosage levels sufficient to deliver from about 0.001 mg/kg toabout 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, fromabout 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10mg/kg, and from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

Suitable dosage amounts and dosing regimens can be determined by theattending physician and may depend on the particular condition beingtreated, the severity of the condition as well as the general age,health and weight of the subject. It will be appreciated that doseranges as described herein provide guidance for the administration ofprovided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

The active ingredient may be administered in a single dose or a seriesof doses. While it is possible for the active ingredient to beadministered alone, it is preferable to present it as a composition,preferably as a pharmaceutical composition. The formulation of suchcompositions is well known to those skilled in the art. The compositionmay contain any suitable carriers, diluents or excipients. These includeall conventional solvents, dispersion media, fillers, solid carriers,coatings, antifungal and antibacterial agents, dermal penetrationagents, surfactants, isotonic and absorption agents and the like. Itwill be understood that the compositions of the invention may alsoinclude other supplementary physiologically active agents.

The compounds, salts, polymorphs, and pharmaceutical compositionsdescribed herein can be used in combination therapy with one or moreadditional therapeutic agents. For combination treatment with more thanone active agent, where the active agents are in separate dosageformulations, the active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of the otheragent.

When co-administered with other agents, e.g., when co-administered withanother anti-anxiety or anti-depressant medication, an effective amountof the second agent will depend on the type of drug used. Suitabledosages are known for approved agents and can be adjusted by the skilledartisan according to the condition of the subject, the type ofcondition(s) being treated and the amount of a compound described hereinbeing used. In cases where no amount is expressly noted, an effectiveamount should be assumed. For example, compounds described herein can beadministered to a subject in a dosage range from between about 0.01 toabout 10,000 mg/kg body weight/day, about 0.01 to about 5000 mg/kg bodyweight/day, about 0.01 to about 3000 mg/kg body weight/day, about 0.01to about 1000 mg/kg body weight/day, about 0.01 to about 500 mg/kg bodyweight/day, about 0.01 to about 300 mg/kg body weight/day, about 0.01 toabout 100 mg/kg body weight/day.

When combination therapy is employed, an effective amount can beachieved using a first amount of compound 1, or a salt or polymorphthereof, and a second amount of an additional suitable therapeuticagent.

In certain embodiments, compound 1 or a salt or polymorph thereof asdescribed herein, or a pharmaceutically acceptable salt thereof, and theadditional therapeutic agent are each administered in an effectiveamount (i.e., each in an amount which would be therapeutically effectiveif administered alone). In other embodiments, compound 1, or a salt orpolymorph thereof as described herein, or a pharmaceutically acceptablesalt thereof, and the additional therapeutic agent are each administeredin an amount which alone does not provide a therapeutic effect (asub-therapeutic dose). In yet other embodiments, compound 1, or a saltor polymorph thereof as described herein, can be administered in aneffective amount, while the additional therapeutic agent is administeredin a sub-therapeutic dose. In still other embodiments, compound 1, or asalt or polymorph thereof as described herein, can be administered in asub-therapeutic dose, while the additional therapeutic agent isadministered in an effective amount.

Co-administration encompasses administration of the first and secondamounts of the compounds in an essentially simultaneous manner, such asin a single pharmaceutical composition, for example, capsule or tablethaving a fixed ratio of first and second amounts, or in multiple,separate capsules or tablets for each. In addition, suchco-administration also encompasses use of each compound in a sequentialmanner in either order. When co-administration involves the separateadministration of the first amount of compound 1 or a salt or polymorphthereof as described herein, and a second amount of an additionaltherapeutic agent, the compounds are administered sufficiently close intime to have the desired therapeutic effect. For example, the period oftime between each administration which can result in the desiredtherapeutic effect, can range from minutes to hours and can bedetermined taking into account the properties of each compound such aspotency, solubility, bioavailability, plasma half-life, and kineticprofile. For example, compound 1, or a salt or polymorph thereof asdescribed herein, and the second therapeutic agent can be administeredin any order within about 24 hours of each other, within about 16 hoursof each other, within about 8 hours of each other, within about 4 hoursof each other, within about 1 hour of each other or within about 30minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeuticagent such as a compound described herein) can be administered prior to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksbefore), concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapy to a subject.

Examples of therapeutic agents that may be combined with compound 1, ora salt form or polymorph thereof, either administered separately or inthe same pharmaceutical composition, include, but are not limited to,muscle relaxants, anticonvulsants, hypnotics, anaesthetics, analgesics,cholinergics, antidepressants, mood stabilisers, and anxiolytics.

In certain embodiments, a second therapeutic agent is a SSRI selectedfrom the following: citalopram (Celexa, Cipramil, Cipram, Dalsan,Recital, Emocal, Sepram, Seroprnm, Citox, Cital), dapoxetine (Priligy),escitalopram (Lexapro, Cipralex, Seroplex, Esertia), fluoxetine (Prozac,Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin(EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)),fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox),paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius,Rexetin, Xetanor, Paroxat, Loxamine, Deparoc), sertraline (Zoloft,Lustral, Serlain, Asentra), and vilazodone (Viibryd).

In certain embodiments, a second therapeutic agent is a tetracyclicantidepressant (TeCA) selected from the group consisting of: amoxapine(Amokisan, Asendin, Asendis, Defanyl, Demolox, Moxadil), maprotiline(Deprilept, Ludiomil, Psymion), mazindol (Mazanor, Sanorex), mianselin(Bolvidon, Depnon, Norval, Tolvon), mirtazapine (Remeron, Avanza,Zispin, Miro), and setiptiline (Tecipul).

In certain embodiments, a second therapeutic agent is aserotonin-noradrenaline reuptake inhibitor (SNRI) selected from thegroup consisting of: desvenlafaxine (Pristiq), duloxetine (Cymbalta,Ariclaim, Xeristar, Yentreve, Duzela), milnacipran (Ixel, Savella,Dalcipran, Toledomin), and venlafaxine (Effexor, Efexor).

In certain embodiments, a second therapeutic agent is a Noradrenalinereuptake inhibitor (NRI) selected from the group consisting of:atomoxetine (Tomoxetine, Strattera, Attentin), mazindol (Mazanor,Sanorex), reboxetine (Edronax, Norebox, Prolift, Solvex, Davedax,Vestra), and viloxazine (Vivalan, Emovit, Vivarint, Vicilan).

In certain embodiments, a second therapeutic agent is a monoamineoxidase inhibitor (MAOI) selected from the group consisting of: benmoxin(Nerusil, Neuralex), hydralazine (Apresoline), iproclozide (Sursum),iproniazid (Marsilid, prozid, Ipronid, Rivivol, Propilniazida),isocarboxazid (Marplan), isoniazid (Laniazid, Nydrazid), mebanazine(Actomol), nialamide (Niamid), octamoxin (Ximaol, Nimaol), phenelzine(Nardil, Nardelzine), pheniprazine (Catron), phenoxypropazine (Drazine),pivalylbenzhydrazine (Tersavid), procarbazine (Matulane, Natulan,Indicarb), caroxazone (Surodil, Timostenil), echinopsidine (Adepren),furazolidone (Furoxone, Dependal-M), linezolid (Zyvox, Zyvoxam,Zyvoxid), tranylcypromine (Parnate, Jatrosom), brofaromine (Consonar),metralindole (Inkazan), minaprine (Cantor), moclobemide (Aurorix,Manerix), pirlindole (Pirazidol), toloxatone (Humoryl), lazabemide(Pakio, Tempium), pargyline (Eutonyl), rasagiline (Azilect), andselegiline (Deprenyl, Eldepryl, Emsam).

In certain embodiments, a second therapeutic agent is a tricyclicantidepressant (TCA) selected from the group consisting of:amitriptyline (Tryptomer, Elavil, Tryptizol, Laroxyl, Sarotex,Lentizol), butriptyline (Evadene, Evadyne, Evasidol, Centrolese),clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dosulepin(Prothiaden, Dothep, Thaden and Dopress), doxepin (Aponal, Adapine,Doxal, Deptran, Sinquan, Sinequan, Zonalon, Xepin, Silenor), imipramine(Antideprin, Deprimin, Deprinol, Depsol, Depsonil, Dynaprin, Eupramin,hnipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil), lofepramine(Gamanil, Tymelyt, Lomont), nortriptyline (Sensoval, Aventyl, Pamelor,Norpress, Allegron, Noritren, Nortrilen), Protriptyline (Vivactil), andtrimipramine (Sunnontil, Rhotrimine, Stangyl).

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. These examples are forillustrative purposes only and are not to be construed as limiting thisinvention in any manner.

Example 1. General Methods of Instrumental Measurements

FT-Raman Spectroscopy. Bruker RFS100 with OPUS 6.5 software or Multi-RAMwith OPUS 7.0 software; Nd:YAG 1064-nm excitation, Ge detector, 3500-100cm⁻¹ range; typical measurement conditions: 50-300 mW nominal laserpower, 64-128 scans, 2 cm⁻¹ resolution.

XRPD. Broker D8; reflection geometry, Bragg-Brentano; Cu—K_(α)radiation, 40 kV/40 mA; variable divergence slit; LynxEye detector with3° window; 0.02° 2θ step size; 37 s step time. The samples were rotatedduring the measurement. Sample preparation: The samples were generallyprepared without any special treatment other than the application ofslight pressure to get a flat surface. Silicon single crystal sampleholder, 0.1 mm deep.

¹H-NMR. Bruker DPX300 spectrometer; proton frequency of 300.13 MHz; 30°excitation pulse; recycle delay of 1 s; accumulation of 16 scans;deuterated DMSO as the solvent; solvent peak used for referencing;chemical shifts reported on the TMS scale.

TG-FTIR. Netzsch Thermo-Microbalance TG 209 with Bruker FT-IRSpectrometer Vector 22; aluminum crucible (with micro-hole), N₂atmosphere, 10 K/min heating rate, 25-250° C. or 25-350° C. range.

DSC. Perkin Elmer DSC 7; closed gold crucibles, sample filled in an N₂environment, 10 K/min heating rate, −50 to 250° C. range, at timesquench cooling (at −200 K min⁻¹) to −50° C. between scans.

DVS. Projekt Messtechnik Sorptions Prüf system SPS 11-100 n or SurfaceMeasurement Systems DVS-1. The sample was placed on an aluminum orplatinum holder on top of a microbalance and allowed to equilibrate for2 h at 50% r.h. before starting one of two pre-defined humidityprograms:

(1) 2 h at 50% r.h.;

(2) 50→0% r.h. (5%/h); 5 h at 0% r.h.;

(3) 0→95% r.h. (5%/h); 5 h at 95% r.h.; and

(4) 95→50% r.h. (5%/h); 2 h at 50% r.h.;

or

(1) 2 h at 50% r.h.;

(2) 50→95% r.h. (5%/h); 5 h at 95% r.h.;

(3) 95→0% r.h. (5/o/h); 5 h at 0% r.h.; and

(4) 0→50% r.h. (5%/h); 2 h at 50% r.h.

The hygroscopicity was classified based on the mass gain at 85% r.h.relative to the initial mass as follows: deliquescent (sufficient wateradsorbed to form a liquid), very hygroscopic (mass increase of ≧15%),hygroscopic (mass increase <15% and ≧2%), slightly hygroscopic (massincrease <2% and ≧0.2%), or non-hygroscopic (mass increase <0.2%).

Solvents. For all experiments, Fluka, Merck or ABCR analytical gradesolvents were used.

Approximate Solubility Determination. Approximate solubilities weredetermined by a stepwise dilution of a suspension of about 10 mg ofsubstance in 0.05 mL of solvent. If the substance was not dissolved byaddition of a total of >10 mL solvent, the solubility is indicated as <1mg/mL. Due to the experimental error inherent in this method, thesolubility values are intended to be regarded as rough estimates and areto be used solely for the design of crystallization experiments.

Aqueous Solubility Determination. Approximately 0.3 mL of doublydistilled water was added to 3-10 mg of the substance to be measured.The resulting suspension/solution was equilibrated in atemperature-controlled Eppendorf Thermomixer Comfort shaker for 2 h at25° C. at a shaking rate of 500 rpm. The solid phase was recovered byfilter centrifugation (0.10-μm PVDF membrane) and examined by FT-Ramanspectroscopy. The pH of the corresponding solution was determined with aMetrohm 713 pH meter. The concentration of the solution was determinedby HPLC (see below).

HPLC: For the aqueous solubility measurements the HPLC method given inTable 77 was used. Standard solutions of the SP196-FD-P1 free drug ofcompound 1 and the L-malate salt of compound 1 (SP196-MLA-P4) wereprepared in the concentration range of 0.2-0.05 mg/mL for theconstruction of a calibration curve.

TABLE 77 HPLC method used for solubility determinations. InstrumentAgilent 1100 series Column Waters Xterra C18, 100 × 4.6 mm, 5 μm(FK-CC01E) Mobile Phase A H₂O + 0.1% TFA Mobile Phase B MeCN Referenceconc. 0.2-0.05 mg/mL Retention time 10.48 min Gradient  0 min 95% A 5% B20 min  5% A 95% B  20.5 min   95% A 5% B 22 min 95% A 5% B Flow 1.00mL/min Injection Volume 10 μL Column temp. 25° C. Wavelength 240 nm

Example 2. General Methods of Crystallization and Drying

Sixty solvent-based crystallization and drying experiments were carriedout with the aim of identifying the thermodynamically stable polymorphat room temperature as well as hydrates, solvates, and the most relevantmetastable forms.

Several different crystallization methods were used including suspensionequilibration (Example 3), cooling crystallization (Example 4),evaporation (Example 5), precipitation (Example 6), vapor diffusion(Example 7), and reverse vapor diffusion (Example 7). Experimentsinvolving drying and desolvation of solvates/hydrates were alsoperformed (Example 8).

A crystalline form of compound 1 was provided; PP445-P1 is an exemplarybatch. The amorphous form of compound 1 was prepared (Example 10) andwas used as a starting material for crystallization experiments inaddition to crystalline compound 1.

Solvents were chosen with respect to a diversity of theirphysico-chemical parameters such as solubility, polarity,proticity/aproticity, volatility, etc. Several experiments were carriedout in water/solvent mixtures with various water activities to searchfor hydrates. Other experiments were carried out in solvents that hadbeen dried over molecular sieves, in order to ensure that they were freeof water.

Special care was taken to ensure that a large variety of crystallizationtechniques and solvent properties was explored.

The obtained solid forms of compound 1 were characterized by XRPD,FT-Raman, DSC, DVS, TG-FTIR, ¹H-NMR, melting point, solubility, and/orstability. In addition, the peaks in the XRPD patterns were determinedand the patterns then classified using the PANalytical X'Pert (HighscorePlus) software.

Example 3. General Methods of Suspension Equilibration

Suspension equilibration experiments in a variety of different solventsand solvent mixtures were carried out at various temperatures.

This solvent-based crystallization method is aimed at obtaining thethermodynamically stable polymorphic form (or hydrate or solvate) underthe applied conditions (solvent system and temperature).

The solvents and solvent mixtures were chosen based on the solubility ofthe compound (ideally about 2-30 mg/mL) and the physicochemicalproperties of the solvents.

Several experiments were carried out in water/solvent mixtures withvarious water activities in the search for hydrates. For otherexperiments solvents that had been dried over molecular sieves were usedin order to ensure that they were free of water.

The goal of the experiments (22-23° C., 14-day duration, solvent=MeOH,EtOH, MeCN, acetone, EtOAc, THF, 2-PrOH, 9:1 THF/H₂O, 93:7 MeCN/H₂O, or95:5 2-PrOH/H₂O) was to find the most stable polymorphic form ofcompound 1 at room temperature with a high probability.

The experiments at elevated temperatures (50° C., 4-day duration,solvent=acetone, DMF, THF, or EtOH) should provide an indication ofwhether a different form is more stable at this temperature, which canbe particularly important for developing a controlled coolingcrystallization process for the final step of API production. Inaddition, the use of high temperatures can help overcome kineticbarriers to polymorphic interconversion.

The experiments at 5° C. were carried out to search for solvated (andadditional hydrated) forms of compound 1 since experiments at lowtemperatures are conducive to solvate and hydrate formation.

The amorphous material was used as the starting material for severalsuspension equilibration experiments (temperature=5° C., 30° C., 75° C.,or 90° C.; duration=1 d, 5 d, or 7 d; solvent=THF, 96:4 acetone/H₂O,98.5/1.5 acetone/H₂O, 2-PrOH, or water). Since the amorphous form is ina higher energy state than the crystalline form of the starting materialcompound 1, potential kinetic barriers might not poses as much of ahindrance for a transformation. The amorphous form of compound 1 wasused as starting material for experiments to determine the stabilityrange of compound 1 by equilibration at various water activity levels.

Upon completion of the suspension equilibration experiments, therecovered products were examined by Raman spectroscopy both immediatelyafter filtration and after 30 min of drying under vacuum at roomtemperature. Such a procedure can permit the identification of labilesolvates that rapidly convert into other forms on the laboratory scale.

Example 4. General Methods of Cooling Crystallizations from HotSolutions

Cooling crystallizations from hot solutions can not only yield thethermodynamically stable form but also produce metastable forms when thecrystallization occurs spontaneously and rapidly. In addition,application of heat can change the energetics and mobility of themolecules in solution. Thus different configurations (i.e.,conformations and solution-based clusters) might be accessible, leadingto the crystallization of different polymorphic forms.

Solvents and solvent mixtures with known (or estimated) low solubilities(e.g., 1-5 mg/mL) at room temperature are ideal for this type ofexperiment. In addition, as T_(max) is limited by the boiling point ofthe solvent (or by the lowest boiling point from a mixture of solvents),solvents with different boiling points were used in order to explore alarger temperature range.

A summary is given in Table 78.

TABLE 78 Cooling experiments starting with PP445-P1. Solvent/Mixture^(a)T_(max) T_(min) Cooling dioxane/toluene 90° C. 0° C.  0.15 K/min2PrOH/H₂O 75° C. 0° C. 0.125 K/min EtOH/heptane 75° C. 0° C. 0.125 K/minTHF/IPE 60° C. 0° C.  0.10 K/min Dioxane 85° C. 0° C. fast MeCN 80° C.0° C. fast^(b) EtOAc 75° C. 0° C. fast^(b) ^(a)Organic solvents weredried over molecular sieves. ^(b)Precipitation only after partialevaporation of solvent.

Example 5. General Methods of Evaporation

Evaporation is another crystallization method that can lead to eitherfast or slow precipitation depending on the speed of solvent removal.Thus, evaporations were carried out under N₂ flow or ambient conditions(open vial).

All evaporation experiments were carried out using the amorphous form ofcompound 1 as the starting material (under N₂ flow or in open vial;temperature=room temperature (r.t.); solvent=MeCN, EtOAc, DCM, or methylethyl ketone (MEK)).

Example 6. General Methods of Precipitation

Precipitation experiments can be carried out either by adding anantisolvent (AS) slowly or quickly into a solution of the compound or byadding a solution of the compound slowly or quickly into a bath ofantisolvent. These different techniques can potentially lead todifferent forms even when using the same solvent mixture.

Solvents with a relative high solubility (ideally about 10-50 mg/mL) andantisolvents with a low solubility (e.g., <1 mg/mL) were chosen. Inaddition, the solvent and antisolvent pair should be freely miscible. Toavoid possible solvate and/or hydrate formation, precipitationexperiments can also be carried out at elevated temperatures.Precipitation experiments were carried out with the crystalline compound1 starting material (Table 79).

TABLE 79 Precipitation experiments with the crystalline startingmaterial compound 1 (sample PP445-P1). Solvent Antisolvent T Conditionspyridine TBME r.t. AS added to solution dioxane heptane 40° C. AS addedto solution 1BuOH toluene 40° C. AS added to solution DCM hexane r.t.solution added to AS acetone DEE  5° C. solution added to AS

In addition, attempts were made to reproduce Form SUC-P3(solvent=acetone, temperature=r.t., duration=1 d). The experimentsSP196-SUC-P3 and SP196-MLA-P3 were repeated without the use of thesuccinic acid or L-malic acid salt former (as PP445-P38). Thespontaneous precipitation from a saturated acetone solution resulted inForm C.

Next, in experiment PP445-P39, a saturated acetone solution was seededwith a small amount of From SUC-P3. A suspension formed. However, theobtained solid material also corresponds to Form C and not to FormSUC-P3. Thus, reproduction of Form SUC-P3 without the use of a saltformer was not possible.

Considering all results and data, it was concluded that Form SUC-P3 isnot a polymorph of the free drug but a succinate salt with a similarlattice structure to a malate salt.

Example 7. General Methods of Vapor Diffusion and Reverse VaporDiffusion

Vapor diffusion is a slow crystallization method aimed at obtainingcrystalline material of the stable form under the applied conditions(solvent system and temperature). A volatile antisolvent is allowed toslowly diffuse into a solution of the compound and thereby to graduallyreduce the solubility in the solvent mixture, leading to saturation,supersaturation, and, ultimately, crystallization. This type ofcrystallization experiment can take place over the course of severalweeks.

Reverse vapor diffusion experiments are performed by dissolving the APIin a solvent/antisolvent mixture in which the solvent is the morevolatile component. Partial evaporation is then allowed to occur, andsince the more volatile solvent evaporates faster, the solubility shoulddecrease over time, leading to a slow build-up of supersaturation andprecipitation.

By using both complementary techniques, a wide solvent space can beexplored. Solvent/antisolvent pairs with a large difference in theirvapor pressures were chosen. Solvents ideally have a relatively highsolubility (e.g., about 10 mg/mL), while antisolvents have a lowsolubility (e.g., <1 mg/mL).

The vapor diffusion and reverse vapor diffusion experiments aresummarized in Table 80 and Table 81, respectively.

TABLE 80 Vapor diffusion experiments starting with PP445-P1. SolventAntisolvent Condition DMSO TBME r.t. → 4° C. DMF DEE r.t. pyridinehexane r.t. 1BuOH heptane r.t. → 4° C.

TABLE 81 Reverse vapor diffusion experiments starting with PP445-P1.Solvent Antisolvent Condition THF H₂O r.t. DCM toluene r.t. MEK heptane70° C. MeOH toluene 60° C. acetone hexane 15° C.

Example 8. General Methods of Drying and Desolvation

Drying and desolvation experiments were carried out with at least onesample of each obtained solvate and hydrate (including the startingmaterial compound 1).

The solvated/hydrated forms were either dried under vacuum (<5 mbar) atr.t. or elevated temperatures, or suspended and equilibrated in anon-solvate forming solvent/solvent mixture at various temperatures.

Using a variety of starting materials (i.e., different solvates) withpossibly varying conformations and/or different intra- andintermolecular interactions, can lead to the formation of new anhydrouspolymorphic forms.

Summaries of the experiments are provided in Table 82 and Table 83.

TABLE 82 Drying under vacuum of the obtained solvates/hydrates. FormTemperature Condition E (MeOH solvate) r.t. overnight F (EtOH solvate)r.t. overnight G (2-PrOH solvate) r.t. overnight H (1-BuOH solvate) r.t.3 d I (THF solvate) 40° C. overnight J (EtOAc solvate) r.t. overnight K(dioxane solvate) r.t. 3 d L (pyridine solvate) 40° C. overnight

TABLE 83 Desolvation experiment by suspension of the solvates/hydratesin non-solvate forming solvents. Form Conditions Solvent M (DMSOsolvate) 5 d at 35° C. 1:1 acetone/TBME L (pyridine solvate) 5 d at 35°C. 1:1 DCM/hexane I (THF solvate) 5 d at 35° C. EtOAc F (EtOH solvate) 7d at 90° C. heptane G (2-PrOH solvate) 7 d at 110° C. i-BuOAc G (2-PrOHsolvate) 2 d at 130° C. aniline

Example 9. General Methods of Salt Screening

For the salt screening evaporation experiment stock solutions of thefree drug compound 1 were prepared in THF, MeCN, 2-PrOH, and acetone.Stock solutions of most salt formers were also prepared in THF, MeCN,2-PrOH, and acetone. Due to low solubility in organic solvents, stocksolutions of some salt formers were prepared in H₂O only (Table 84).

TABLE 84 Concentrations (in mol/l) of the free drug 1 and the saltformers (FUM, MLA, MLE, and SUC) instock solutions. THF MeCN 2-PrOHacetone Free drug 1 0.038 0.019 0.021 0.021 FUM (fumaric acid) 0.050 —0.050 0.037 MLA (L-malic acid) 0.050 0.050 0.050 0.050 MLE (maleic acid)0.050 0.050 0.050 0.050 SUC (succinic acid) 0.050 0.043 0.050 0.050

Salts were prepared by mixing the stoichiometric volumes of each stocksolution (free drug and corresponding salt former) according to themicrotiter plate layout with a total sample volume about 200 μL.

Crystallization was performed by evaporation of the solvents under N₂flow at room temperature. The resulting solids were examined by Ramanmicroscopy. Two Raman spectra and microscopic images were collected foreach obtained residue.

For the phase equilibration (slurry) experiments, a second set of foursolvents was selected: heptane, EtOAc, diisopropyl ether (IPE), andtoluene. To the residues of the evaporation experiments 100 μL ofsolvent were added: heptane to columns 1 to 3 (wells A1 to H3), EtOAc tocolumns 4 to 6 (wells A4 to H6), IPE to columns 7-9 (wells A7 to H9),and toluene to columns 10 to 12 (wells A10 to H12). The microtiter platewas shaken on an Eppendorf Thermo-Mixer at 500 rpm for 3 days, with atemperature cycling program (20-30° C.). The solvents were againevaporated at r.t. under controlled N₂ flow. The resulting solids wereexamined by Raman microscopy. Two Raman spectra and microscopic imageswere collected for each residue.

Example 10. Preparation of Form A

Methods of preparing amorphous Form A are illustrated in Table 85. Thesolid material obtained from a fast evaporation experiment usingcompound 1 under N₂ flow at r.t. (PP442-P22) shows a diffractogram withseveral broad, unresolved features from −3°2θ to 30° 2θ on top of abroad halo from ˜10° 2θ to 30° 2θ which is characteristic for amorphousmaterial (FIG. 1). Some structure might have been retained in thissample.

TABLE 85 Experiments aimed at preparing Form A of compound 1. SampleMethod Conditions Result PP445-P22 fast evaporation under N₂ at r.t.mainly amorphous from DCM PP445-P23 quench cooling of heated to 180° C.;amorphous melt cooled in ice

Amorphous Form A was successfully prepared by quench cooling the melt(PP445-P23) (Table 1). The diffractogram of the obtained glassysubstance (FIG. 1) shows no distinct peaks but only the broad halo from˜10° 2θ to 30° 2θ that is characteristic for amorphous material.

The FT-Raman spectrum of PP445-P23 (FIG. 2) shows relatively broad peakscompared to the crystalline Form C. It is defined as the referencespectrum of Form A.

The amorphous material appears to be stable for at least 5 days underambient conditions, as it was unchanged after re-examination by XRPD(data not shown).

Example 11. Preparation and Characterization of Form C

Form C may be prepared according to the following method: A sample ofcompound 1 (10 mg) was placed in a small glass test tube (approx. 8 mmdiameter), EtOH (250 μL; AR grade at r.t.) was added, and the resultingmixture was warmed (hair dryer) until all of the solid material wasfully dissolved. The solution was then diluted with warm water (250 μLMilli-Q, pre-warmed to 30-40° C.). The resulting clear solution wasallowed to cool to room temperature, leading to the formation of asolid. The solid was isolated by decanting the mother liquor and thenwashing the remaining solid with a small amount (100 μL) of 50% aqueousethanol (50:50 mix of AR grade EtOH and Milli-Q water; r.t.). The finalsolid material was dried in a vacuum desiccator to yield Form C.

Form C may alternatively be prepared according to the following method.20 g of compound 1 was suspended in 200 ml of acetone (reagent grade)and heated to 50-55° C. with vigorous stirring (using magnetic bar in a2000-ml flask). Within 30 m of stirring at 50-55° C. the suspensionturned into a very thick cake. 100 ml of acetone was added to the cakewhile keeping reaction temperature to 50-55° C. (stirring startedagain). Addition of acetone was repeated three times within 30 minutes(about 8 min interval). The resulting suspension was stirred for 2 h at50-55° C. The reaction vessel was removed from oil-bath and cooled tor.t. (˜30 min) and solid separated was filtered, dried, and powdered toyield Form C.

An FT-Raman spectrum is shown in FIG. 4.

The XRPD patterns are shown in FIG. 3.

The TG-FTIR (sample PP445-P13, FIG. 7) shows the loss of ˜0.7 wt % DMF(<0.05 eq.) gradually from 50° C. to 250° C., most likely residualsolvent due to incomplete drying (the sample was dried under vacuum for1 h). Decomposition starts at temperatures >250° C.

The ¹H-NMR spectrum agrees with the structure of compound 1 (FIG. 69).

The microscopic image of a sample of Form C (sample PP445-P38, FIG. 8)shows very fine hair or needles.

The DSC thermogram (sample PP445-P13, FIG. 5) shows a sharp endothermicevent with a peak at T_(max)=212.4° C. (ΔH=99.0 J/g), likelycorresponding to melting, and no further events up to 250° C.

The DVS isotherm (sample PP445-P13, FIG. 6) shows a reversible mass lossof ˜0.3 wt % upon decreasing the relative humidity (r.h.) from 50% r.h.to 0%. Equilibrium was reached at 0% r.h. Upon increasing the relativehumidity from 50% r.h. to 95% r.h. a mass increase of ˜0.6 wt % isobserved. Equilibrium was reached at 95% r.h. Upon decreasing therelative humidity from 95% r.h. to 50% r.h., a mass loss occurred andthe final mass is equal to the starting mass.

The mass increase of ˜0.2 wt % from 50% to 85% r.h. classifies thematerial as slightly hygroscopic.

The FT-Raman spectrum of the material after the DVS measurementcorresponds to the spectrum of the material before the DVS measurement.

The aqueous solubility of Form C (sample PP445-P43) is 0.04 mg/mL (atpH=7.5 of saturated solution) after 2 h equilibration at 25° C. TheFT-Raman spectrum of the solid residue is unchanged.

Thus, Form C corresponds to a crystalline, anhydrous, slightlyhygroscopic polymorph of compound 1. Form C is a thermodynamicallystable polymorph of compound 1 at least in the temperature range from25° C. to 60° C.

Example 12. Preparation and Characterization of Form D

Form D (such as sample PP445-P2-T1) was obtained by drying Form E undervacuum (<5 mbar) at r.t. overnight.

The FT-Raman spectrum of Form D is given in FIG. 10.

The XRPD pattern (FIG. 9) is changed compared to the methanol solvate(Form E) and does not correspond to the starting material (compound 1)or to the anhydrous Form C.

The TG-FTIR thermogram (FIG. 12) shows no significant mass loss (˜0.2 wt% H₂O) from 50° C. to 180° C., and decomposition at temperatures >250°C.

The ¹H-NMR spectrum (FIG. 70) agrees with the given structure ofcompound 1 without any solvent content.

The DSC thermogram (FIG. 11) shows two overlapping endothermic eventswith peaks at T_(max)=162.0° C. (ΔH≈27.8 J/g) and T_(max)=175.6° C.(ΔH≈24.3 J/g), followed by a third endothermic event with a peak atT_(max)=204.5° C. (ΔH=13.7 J/g).

Thus, Form D corresponds to a crystalline, anhydrous polymorph ofcompound 1. Form D may be thermodynamically less stable than Form C atleast in the temperature range from 25° C. to 60° C.

Example 13. Preparation and Characterization of Form E

Form E (such as sample PP445-P2) was prepared from a suspensionequilibration experiment on compound 1 at 23° C. in MeOH. In one set ofexperiments, 99.2 mg of compound 1 (sample PP445-P1) were suspended in0.5 mL of MeOH; the suspension was equilibrated at 23° C. and 500 rpm;after 14 days a solid was recovered by filter centrifugation (0.2-μmPTFE membrane) to yield Form E (sample PP445-P2).

The FT-Raman spectrum and XRPD pattern of Form E are given in FIG. 14and FIG. 13, respectively.

The TG-FTIR thermogram (FIG. 15) shows the loss of ˜4.8 wt % MeOH andH₂O (≦0.65 eq. MeOH) from 50° C. to 200° C. and decomposition attemperatures >250° C.

These results indicate that Form B is a methanol solvate of compound 1.

Example 14. Dying Experiments on Form E

A sample of Form E (PP445-P2) was dried in an attempt to desolvate it(as sample PP445-P2-T1). The solid material PP445-P2 was stored undervacuum (<5 mbar) at r.t. overnight. The solvents included in Form Ebefore drying were 4.8% MeOH and H₂O. The solvent included in the sampleof Form E after drying was 0.2% H₂O. The FT-Raman spectrum and XRPDpattern of the dried sample corresponded to Form D.

Example 15. Preparation and Characterization of Form F

Form F (such as samples PP445-P3 and PP445-P27) was obtained fromsuspension equilibration experiments on compound 1 at 23° C. or 50° C.in EtOH. In one set of experiments, 99.2 mg of compound 1 (samplePP445-P1) were suspended in 0.5 mL of EtOH; suspension at 23° C. and 500rpm; after 14 days recovered solid by filter centrifugation (0.2-μm PTFEmembrane to yield Form F (sample PP445-P3).

The FT-Raman spectrum is given in FIG. 17. The XRPD pattern is shown inFIG. 16.

The TG-FTIR (sample PP445-P27, FIG. 18) shows the loss of ˜7.5 wt % EtOH(˜0.75 eq.) from 50° C. to 180° C., further loss of ˜1.4 wt % EtOH from170° C. to 250° C. and decomposition at temperatures >250° C. The samplehad been dried under vacuum at r.t, for 1 h before the measurement.Thus, most of the EtOH content (boiling point=78° C.) is likely boundwithin the structure.

These results indicate Form F is an ethanol solvate of compound 1.

Example 16. Drying Experiments on Form F

A sample of Form F (PP445-P27) was dried in an attempt to desolvate it(as sample PP445-P27-T1). The solid material PP445-P27 was stored undervacuum (<5 mbar) at r.t. overnight. The solvent included in the samplebefore and after drying was 8.9% EtOH and 2.7% EtOH, respectively.

The XRPD pattern of the dried sample shows only a few broad peaksindicating that the dried sample is of lower crystallinity compared tothe material before drying.

The TG-FTIR thermogram shows the loss of ˜2.2 wt % EtOH (and some H₂O)from 50° C. to 160° C. and a second loss of ˜0.5 wt % EtOH from 160° C.to 240° C. Decomposition starts at temperatures >250° C.

Thus, a partial desolvation has likely occurred parallel to a break-downof the crystal structure of Form F. No transformation into a known ornew anhydrous form was observed.

Example 17. Preparation and Characterization of Form G

Form G (such as sample PP445-P8) was prepared from a suspensionequilibration experiment on compound 1 at 23° C. in 2-PrOH. In one setof experiments, 99.0 mg of compound 1 (sample PP445-P1) were suspendedin 0.5 mL of 2PrOH; equilibrated suspension at 23° C. and 500 rpm; afterseveral days added 0.5 mL solvent; after a total of 14 days recoveredsolid by filter centrifugation (0.2-μm PTFE membrane) to yield Form G(sample PP445-P8).

The FT-Raman spectrum and XRPD pattern of Form G are given in FIG. 20and FIG. 19, respectively.

The TG-FTIR thermogram (FIG. 21) shows the loss of ˜4.5 wt % 2-PrOH(˜0.3 eq.) from 50° C. to 220° C. and decomposition attemperatures >280° C. The sample was dried under vacuum at r.t. for 1 hbefore the measurement. Thus, most of the 2-PrOH content (boiling point(b.p.)=82° C.) is likely bound within the structure.

These results indicate that Form G is a 2-propanol solvate of compound1.

Example 18. Drying Experiments on Form G

A sample of Form G (PP445-P8) was dried in an attempt to desolvate it(as sample PP445-P8-T1). The solid material PP445-P8 was stored undervacuum (<5 mbar) at r.t. overnight. The solvent included in the samplebefore and after drying was 4.5% 2-PrOH (with some H₂O) and 4.0% 2-PrOH(with traces of H₂O), respectively.

The XRPD pattern of the dried sample shows only a few broad peaksindicating the dried sample is of lower crystallinity compared to thematerial before drying.

The TG-FTIR thermogramshows the loss of ˜4.0 wt % 2-PrOH (with traces ofH₂O) from 50° C. to 200° C. Decomposition starts at temperatures T>200°C.

Thus, a partial desolvation has likely occurred parallel to a break-downof the crystal structure of Form G. No transformation into a known ornew anhydrous form was observed.

Example 19. Preparation and Characterization of Form H

Form H (such as sample PP445-P37) was obtained from aprecipitation/cooling/evaporation experiment on compound 1 in ˜1:61-butanol/toluene. In one set of experiments, 98.8 mg of compound 1(sample PP445-P1) were suspended in 2.5 mL of 1-BuOH, and the suspensionwas heated to 40° C. Added stepwise 2.5 mL of 1BuOH to obtain clearsolution, and stirred solution at 40° C. After 1 h added slowly andstepwise 30.0 mL of toluene (solution remained clear), stirred solutionat 40° C., and after 2 d observed no changes. Stored solution at 4-5°C., and after 8 d observed no changes. Evaporated solvent under N2 flowat r.t. to obtain Form H as a yellow solid material (sample PP445-P37).

The FT-Raman spectrum and XRPD pattern of Form H are given in FIG. 23and FIG. 22, respectively.

The TG-FTIR thermogram (FIG. 24) shows the loss of ˜6.0 wt % 1-BuOH(˜0.4 eq.) from 50° C. to 220° C. and decomposition attemperatures >250° C. Most of the 1-BuOH content (boiling point=117° C.)is likely bound within the structure.

The ¹H-NMR measurement (FIG. 71) agrees with the given structure. Themeasured sample contains ˜0.3 eq. 1-BuOH which is in good agreement withthe TG-FTIR measurement.

Thus, Form H is likely a 1-butanol solvate of compound 1.

Example 20. Drying Experiments on Form H

A sample of Form H (PP445-P37) was dried in an attempt to desolvate it(as sample PP445-P37-T1). The solid material PP445-P37 was stored undervacuum (<5 mbar) at r.t, for 3 days. The solvent included in the samplebefore and after drying was 6.0% 1-BuOH and 5.4% 1-BuOH, respectively.

The XRPD pattern of the dried sample shows some intensity changescompared to the pattern of the material before drying, but no othersignificant differences.

The TG-FTIR thermogram shows the loss of ˜5.4 wt % 1-BuOH (with someH₂O) from 50° C. to 250° C. Decomposition starts at temperatures >250°C.

Thus, no significant desolvation has occurred. No transformation into aknown or new crystalline form was observed.

Example 21. Preparation and Characterization of Form I

Form I (such as sample PP445-P28) was obtained from a suspensionequilibration experiment at 5° C. in THF starting with the amorphousform of compound 1. In one set of experiments, 98.1 mg of compound 1(sample PP445-P1) were heated to 190° C. and a yellow melt was obtained.Vial was quickly cooled with molten material in ice bath to obtain ayellow glassy material that was proposed to be the amorphous form. Added0.5 mL of THF (dried over 4 Å MS) to obtain light yellow suspension,equilibrated suspension at 5° C. while stirring (as suspension becametoo thick for stirring), and added 2×0.5 mL solvent. After 5 d recoveredsolid by filter centrifugation (0.2-μm PTFE membrane) to obtain Form I(sample PP445-P28).

The FT-Raman spectrum and XRPD pattern of Form I are given in FIG. 26and FIG. 25, respectively.

The TG-FTIR thermogram (FIG. 27) shows the loss of ˜6.3 wt % THF (˜0.4eq.) from 50° C. to 250° C. and decomposition at temperatures>250° C.The sample was dried under vacuum at r.t. for 2 h before themeasurement. Thus, most, if not all, of the THF content (b.p.=66° C.) islikely bound within the structure.

The ¹H-NMR spectrum (FIG. 72) agrees with the given structure. Themeasured sample contains ˜0.4 eq. THF which is in good agreement withthe TG-FTIR measurement.

Thus, Form I is likely a THF solvate of compound 1.

Example 22. Drying Experiments on Form I

A sample of Form I (PP445-P28) was dried in an attempt to desolvate it(as sample PP445-P28-T1). The solid material PP445-P28 was stored undervacuum (<5 mbar) at 40° C. overnight. The solvent included in the samplebefore and after drying was 6.3 wt % THF and 5.0 wt % THF, respectively.

The XRPD pattern of the dried sample shows broader peaks of lowerintensity, indicating that the dried material has lower crystallinitycompared to the sample before drying.

The TG-FTIR thermogram shows the loss of ˜5.0 wt % THF (with traces of1-120) from 50° C. to 250° C. Decomposition starts at temperaturesT>250° C.

Thus, a partial desolvation has likely occurred parallel to a partialbreak-down of the crystal structure of Form 1. No transformation into aknown or new anhydrous form was observed.

Example 23. Preparation and Characterization of Form J

Form J (such as sample PP445-P48) was obtained from a coolingcrystallization of compound 1 in EtOAc. In one set of experiments, 99.2mg of compound 1 (sample PP445-P1) were suspended in 1.0 mL of EtOAc andthe suspension was heated to 75° C. Added stepwise 19.0 mL of EtOAc toobtain a clear solution. Held clear solution at 75° C. for 30 min, thencooled vial with solution quickly in ice bath. Stored sample for ˜4 h inice-bath and overnight at 5° C. Observed clear solution. Partiallyevaporated solvent under N₂ flow in ice-bath and observed noprecipitation. Stored solution overnight at 5° C. Partially evaporatedsolvent under N₂ flow in ice-bath and observed no precipitation. Storedsolution again overnight at 5° C., and observed light yellow suspension.Recovered solid material by vacuum filtration (P4 pore size) to obtainForm J (sample PP445-P48) as a bright yellow material.

The FT-Raman spectrum and XRPD pattern of Form J are given in FIG. 29and FIG. 28, respectively.

The TG-FTIR thermogram (FIG. 30) shows the loss of ˜2.0 wt % EtOAc in astep from 100° C. to 160° C., further loss of ˜1.8 wt % EtOAc from 160°C. to 240° C., and decomposition at temperatures T>250° C. The samplewas dried under vacuum at r.t. for 1 h before the measurement. Thus, theEtOAc content (b.p.=76° C.) is likely bound within the structure, 4 wt %EtOAc correspond to 0.2 eq.

The ¹H-NMR spectrum (FIG. 73) agrees with the given structure. Themeasured sample contains ˜0.2-0.3 eq. EtOAc which is in good agreementwith the TG-FTIR measurement.

Thus, Form J is likely an EtOAc solvate of compound 1.

Example 24. Drying Experiments on Form J

A sample of Form J (PP445-P48) was dried in an attempt to desolvate it(as sample PP445-P48-T1). The solid material PP445-P48 was stored undervacuum (<5 mbar) at r.t. overnight. The solvent included in the samplebefore and after drying was 3.8% EtOAc (with traces of H₂O) and 4.7%EtOAc (with some H₂O), respectively.

The XRPD pattern of the dried sample is unchanged compared to thepattern of the material before drying.

The TG-FTIR thermogram shows the loss of ˜4.7 wt % EtOAc (with somewater) from ˜130° C. to 250° C.

Example 25. Preparation and Characterization of Form K

Form K (such as sample PP445-P46) was obtained from a coolingcrystallization of compound 1 in dioxane. In one set of experiments,99.8 mg of compound 1 (sample PP445-P1) were suspended in 1.0 mL ofdioxane, and the suspension was heated to 80° C. to obtain a clearsolution. Heated clear solution to 85° C., held clear solution at 85° C.for 30 min, and cooled vial with solution quickly in ice bath. Storedsample for 30 min in ice-bath, then warmed to r.t. to obtain asuspension. Stirred suspension at r.t, for 2 h and recovered solidmaterial by filter centrifugation (0.2-μm PTFE membrane) to yield Form K(sample PP445-P46).

The FT-Raman spectrum and XRPD pattern of Form K are given in FIG. 32and FIG. 31, respectively.

The TG-FTIR thermogram (FIG. 33) shows the loss of ˜16.1 wt % dioxane(˜0.9 eq.) from 25° C. to 240° C. and decomposition at temperaturesT>250° C. The sample was dried under vacuum at r.t. for 2 h before themeasurement. Thus, most of the dioxane content (b.p.=100° C.) is likelybound within the structure.

The ¹H-NMR spectrum (FIG. 74) agrees with the given structure. Themeasured sample contains ˜1 eq. dioxane which is in good agreement withthe TG-FTIR measurement.

Thus, Form K is likely a dioxane solvate of compound 1.

Example 26. Drying Experiments on Form K

A sample of Form K (PP445-P46) was dried in an attempt to desolvate it(as sample PP445-P46-T1). The solid material PP445-P46 was stored undervacuum (<5 mbar) at r.t. for 3 days. The solvent included in the samplebefore and after drying was 16.1% dioxane and 7.7% dioxane (with somewater), respectively.

The XRPD pattern of the dried sample shows only few broad peaks of lowintensity indicating that the dried sample is of lower crystallinitycompared to the material before drying.

The TG-FTIR thermogram shows the loss of ˜7.7 wt % dioxane (with somewater) from 50° C. to 230° C. Decomposition starts at temperaturesT>230° C.

Thus, a partial desolvation has likely occurred parallel to a break-downof the crystal structure of Form K. No transformation into a known ornew crystalline form was observed.

Example 27. Preparation and Characterization of Form L

Form L (such as sample PP445-P14) was obtained from a vapor diffusionexperiment on compound 1 involving pyridine and hexane. In one set ofexperiments, 99.7 mg of compound 1 (sample PP445-P1) were dissolved in0.7 mL of pyridine to obtain an almost clear, light yellow solution.Filtered solution through 0.2-μm PTFE membrane and stored open vial inatmosphere saturated with hexane at r.t. Observed white precipitateafter 2 d. Removed liquid phase to give Form L (sample PP445-P14).

The FT-Raman spectrum and XRPD pattern of Form L are given in FIG. 35and FIG. 34, respectively.

The TG-FTIR thermogram (FIG. 36) shows the loss of ˜5.1 wt % pyridine(˜0.3 eq.) from 50° C. to 200° C. and decomposition at temperaturesT>200° C. The sample was dried under vacuum for 1 h before themeasurement. It is likely that at least some of the pyridine content(boiling point of 115° C.) is bound within the structure and this Form Lcorresponds to a pyridine solvate.

The ¹H-NMR spectrum (FIG. 75) agrees with the given structure and apyridine content of ˜0.3 eq, in good agreement with the TG-FTIRmeasurement.

Thus, Form L is likely a pyridine solvate of compound 1.

Example 28. Drying Experiments on Form L

A sample of Form L (PP445-P14) was dried in an attempt to desolvate it(as sample PP445-P14-T1). The solid material was stored under vacuum (<5mbar) at 40° C. overnight. The solvent included in the sample before andafter drying was 5.1% pyridine and 1.4% pyridine, respectively.

The XRPD pattern of the dried sample is unchanged compared to thepattern of the material before drying.

The TG-FTIR thermogram shows the loss of ˜1.4 wt % pyridine from 50° C.to 240° C.

Thus, a partial desolvation has likely occurred, and no change instructure was observed.

The pyridine loss in this dried sample occurs at temperaturessignificantly above the boiling point of 115° C., indicating that atleast some of the pyridine of Form L is bound within the structure.Thus, Form L is likely a pyridine solvate.

Example 29. Preparation and Characterization of Form M

Form M (such as sample PP445-P12) was obtained from a vapor diffusionexperiment on compound 1 involving DMSO and TBME (t-butyl methyl ether).In one set of experiments, 99.7 mg of compound 1 (sample PP445-P1) weredissolved in 5.0 mL of DMSO to obtain an almost clear, light yellowsolution. Filtered solution through 0.2-μm PTFE membrane. Stored openvial in atmosphere saturated with TBME at r.t. and after one monthobserved clear solution. Stored clear solution at 4° C. and after 3 dobserved light yellow precipitate. Let sample warm to r.t. and recoveredprecipitate by vacuum filtration (P4 pore size) to yield Form M (samplePP445-P12) as a light yellow solid material.

The FT-Raman spectrum and XRPD pattern of Form M are given in FIG. 38and FIG. 37, respectively.

The TG-FTIR thermogram (FIG. 39) shows the loss of 17.8 wt % DMSO (withtraces of H₂O) from 50° C. to 350° C. As most of the solvent content(corresponding to ˜1.2 eq.) is lost significantly above the boilingpoint of DMSO (b.p.=189° C.), it is likely that Form M corresponds to aDMSO solvate.

The ¹H-NMR spectrum (FIG. 76) agrees with the structure of the compound1 and contains (in addition to the deuterated d₆-DMSO solvent) ˜1.5 eq.non-deuterated DMSO.

Thus, Form M is likely a DMSO solvate of compound 1.

Example 30. Preparation and Characterization of Form FUM-P3

Form FUM-P3 (such as sample SP196-FUM-P3) was prepared by combiningconcentrated solutions of the fumaric acid (a salt former) and ofcompound 1 (free drug) in acetone (1:1 ratio of fumaric acid to compound1). Spontaneous precipitation of a crystalline solid occurred. Thesolvent was partially evaporated under N₂ flow. The resulting suspensionwas equilibrated between 40° C. and 20° C. overnight. The solid materialwas recovered, dried under vacuum and characterized. In one set ofexperiments, 27.8 mg of fumaric acid were dissolved in 6.0 mL of acetoneto obtain a clear solution. Added 9.6 mL of SP196-FD-stock solution (1:1ratio of FD to sf) to obtain a light yellow solution. The SP196-FD-stocksolution was prepared by dissolving 438.5 mg of compound 1 (samplePP445-P1=sample SP196-FD-P1) in 42.0 mL of acetone, obtaining a clearsolution, and filtering the solution through a 0.2-μm PTFE membrane.Stirred solution at r.t. and after 2 h observed yellow suspension.Partially evaporated solvent under N₂ flow, sonicated suspension for 5min, and equilibrated suspension with temperature cycling (holding for 1h at 20° C., heating in 1 h to 30° C., holding for 1 h at 30° C.,cooling in 1 h to 20° C., repeating) overnight. Recovered solid byfilter centrifugation (0.45-μm PTFE membrane) to yield Form FUM-P3(sample SP196-FUM-P3).

The FT-Raman spectrum of product of the scale-up experiment SP196-FUM-P3corresponds reasonably well to the spectrum of the salt screening lead(SP196-FUM-P2-F1b, FIG. 41).

The XRPD pattern of SP196-FUM-P3 (FIG. 40) confirms the crystallinity ofthe material.

The ¹H-NMR spectrum of SP196-FUM-P3 agrees with the structure of thefree drug and a fumaric acid content of 0.5 eq. (FIG. 77). The samplealso contains ˜0.8 eq. acetone.

The TG-FTIR thermogram of SP196-FUM-P3 (FIG. 44) shows the loss of ˜8.9wt % acetone from 50° C. to 200° C. and decomposition at temperaturesT>200° C. The loss seems to occur in two steps and corresponds to 0.8eq. of acetone assuming a hemi-fumarate salt (2:1 ratio of free drug tosalt former) in agreement with the ¹H-NMR spectrum. As the solvent lossoccurs significantly above the boiling point of acetone (b.p.=56° C.),the solvent is most likely bound within the structure.

The elemental composition analysis complies with a 1:0.5:0.5 ratio offree drug to salt former to acetone solvent content (Table 74).

TABLE 74 Elemental analysis results of SP196-FUM-P3. % C % H % N % O ΣSP196-FUM-P3 (experimental) 64.7 6.1 11.0 17.5 99.3 SP196-FUM-P3 65.26.1 11.1 17.6 100.0 (exp., normalized to 100% C₂₄H₂₆N₄O₃, C₄H₄O₄ 62.95.7 10.5 20.9 100.0 (theoretical 1:1 salt) difference (exp. (norm.) —theo.) 2.3^(a) 0.4^(a) 0.6^(a) −3.3^(a) — C₂₄H₂₆N₄O₃, 0.5 × C₄H₄O₄, 65.36.2 11.1 17.4 100.0 0.5 × C₃H₆O (theoretical 1:0.5 salt with 0.5 eq.acetone) difference (exp. (norm) — theo.) −0.1 −0.1 0.0 0.2 —^(a)Differences that exceed a measurement error of ±0 3%.

Thus, Form FUM-P3 may be a hemi-acetone solvate (0.5 eq. acetone) of ahemi fumarate salt (0.5 eq. salt former).

The DSC thermogram of SP196-FUM-P3 (FIG. 42) shows several endothermicand exothermic events, starting at about 114° C., which are difficult tointerpret and assign at this point. The melting point of the freefumaric acid salt former is at about 287° C.

At the beginning of the DVS experiment (FIG. 43), the sample massdecreased by 1.2 wt % after 2 h equilibration at 50% r.h. Uponincreasing the relative humidity to 95% r.h., the sample mass decreasedfurther by 2.9 wt % (with a total mass loss relative to the startingweight of 4.1 wt %). No equilibrium was reached at 95% r.h. after 5 hequilibration. Upon decreasing the relative humidity from 95% r.h. to 0%r.h. the sample lost 1.7 wt % gradually (with a total mass loss relativeto the starting weight of 5.7 wt %). After 5 h equilibration at 0% r.h.the mass remained stable and equilibrium was reached. Increasing therelative humidity back to 50%, the mass increased by 0.8 wt %. Thus, thefinal mass remained 4.9 wt % below the starting mass.

The FT-Raman spectrum of the material after the DVS measurement (FIG.41) corresponds mainly to the spectrum of the free drug startingmaterial (SP196-FD-P1=PP445-P1, corresponding to a hydrate), withadditional components of the fumarate salt SP196-FUM-P3 and of the freefumaric acid salt former.

Thus, it is conceivable that most (or all) of the acetone (0.5 eq.correspond to 5.7 wt %), and maybe also some of fumaric acid salt former(0.5 eq. correspond to 11.5 wt %) is lost during the DVS cycle (with atotal mass loss of 5.7 wt % at 0% r.h.) and partially replaced by waterto partially transform the salt into the free drug hydrate.

Example 31. Preparation and Characterization of Form FUM-P4

Form FUM-P4 (such as sample SP196-FUM-P4) was prepared by addingcompound 1 (free drug) to a saturated solution of the fumaric acid (saltformer) in THF at 40° C. (in order to prevent formation of a THF solvateof the free drug). The resulting suspension was equilibrated at 40° C.for two days. The solid material was recovered, dried under vacuum, andcharacterized. In one set of experiments, 100.6 mg of fumaric acid weredissolved at 40° C. in 2.0 mL of THE to obtain a clear solution. Addedstepwise solid compound 1 (sample SP196-FD-P1) until light yellowsuspension formed. Equilibrated suspension at 40° C. while stirringovernight. Observed very thin suspension the next day. Added spatula tipof solid SP196-FD-P1 material, continued equilibration at 40° C., andafter 1 d recovered solid by filter centrifugation (0.2-μm PTFEmembrane) to yield Form FUM-P4 (sample SP196-FUM-P4).

The FT-Raman spectrum of the scale-up experiment SP196-FUM-P4 couldcorrespond to the spectrum of the scale-up sample SP196-FUM-P3 with somesmall shifts and differences. The spectrum also contains THF peaks (FIG.46).

The XRPD pattern of the scale-up experiment SP196-FUM-P4 shows broadpeaks with a low resolution. The pattern could correspond to the patternof the scale-up sample SP196-FUM-P3 with some small shifts anddifferences (FIG. 45).

The ¹H-NMR spectrum of the scale-up sample SP196-FUM-P4 agrees with thestructure of the free drug and a fumaric acid salt former content of˜1.0 eq. (FIG. 78). The sample also contains ˜0.8 eq. THF.

The TG-FTIR thermogram of the scale-up sample SP196-FUM-P4 (FIG. 47)shows the loss of ˜11.3 wt % THF from 50° C. to 200° C. anddecomposition at temperatures T>200° C. The loss corresponds to 0.8 eq.of a fumarate salt (1:1 ratio of free drug to salt former) in agreementwith the ¹H-NMR spectrum. As the solvent loss occurs significantly abovethe boiling point of THF (b.p.=66° C.), the solvent is most likely boundwithin the structure.

Thus, the material likely corresponds to a THF solvate of amono-fumarate salt. As the FT-Raman spectrum and XRPD pattern of thisTHF solvate are very similar to the spectrum/pattern of the acetonesolvate (SP196-FUM-P3), these two solvates could beisomorphous/isostructural. However, it is interesting to note, that theacetone solvate (FUM-P3) seems to correspond to a hemi-salt (with 0.5eq. solvent content), while the THF solvate (FUM-P4) is likely amono-salt (with ˜0.8 to ˜1.0 eq. solvent content).

Example 32. Preparation and Characterization of Form MLA-P3

Form MLA-P3 (e.g., sample SP196-MLA-P3) was prepared by combiningconcentrated solutions of L-malic acid (salt former) and of compound 1(free drug) in acetone. The solvent was partially evaporated under N₂flow. After spontaneous precipitation of a crystalline solid, thesuspension was equilibrated between 40° C. and 20° C. overnight. Thesolid material was recovered, dried under vacuum, and characterized. Inone set of experiments, 32.1 mg of L-malic acid were dissolved in 0.3 mLof acetone to obtain a clear solution. Added 9.6 mL of SP196-FD-stocksolution (1:1 ratio of FD to sf) to obtain a light yellow solution.Stirred solution at r.t. and after 2 h observed yellow suspension.Partially evaporated solvent under N₂ flow, sonicated suspension for 5min, and equilibrated suspension with temperature cycling (holding for 1h at 20° C., heating in 1 h to 30° C., holding for 1 h at 30° C.,cooling in 1 h to 20° C., repeating) overnight. Recovered solid byfilter centrifugation (0.2-μm PTFE membrane) to yield Form MLA-P3(sample SP196-MLA-P3).

The FT-Raman spectrum is shown in FIG. 49.

The XRPD pattern of the salt scale-up sample SP196-MLA-P3 (FIG. 48) isvery similar to the pattern of sample SP196-SUC-P3, suggesting thatthese two forms are isomorphic/isostructural. The pattern does notcorrespond to any known pattern of the free drug.

The ¹H-NMR spectrum of SP196-MLA-P3 (FIG. 79) agrees with the structureof the free drug. The sample contains ˜0.3 eq. L-malic acid salt formerand <0.01 eq. acetone solvent residue.

The DSC thermogram (FIG. 50) shows a sharp endothermic event with a peakat T_(max)=212.3° C. (ΔH=94.4 J/g), likely corresponding to melting, andno further event up to 230° C. It has to be noted, that the peak maximumis shifted compared to the DSC thermogram of sample SP196-SUC-P3 (peakat T_(max)=219.1° C.) by ˜7° C.

The similar XRPD patterns of the SP196-MLA-P3 and SP196-SUC-P3 samplessuggested that both correspond not to salts but to one and the same formof the free drug. However, the differences of peaks maxima in the DSCthermograms indicate that these two sample indeed correspond to twodifferent salts (that have nearly identical lattice structures, i.e.,are isomorphic). The similar structure of the L-malic acid and succinicacid salt formers can possibly provide an explanation for the similarityof the XRPD patterns.

Example 33. Preparation and Characterization of Form MLA-P4

Form MLA-P4 (e.g., sample SP196-MLA-P4) was prepared by adding solidcompound 1 (free drug) to a saturated solution of the L-malic acid (saltformer) in MeCN. The resulting suspension was equilibrated undertemperature cycling (20° C.-30° C.) for two days. The solid material wasrecovered, dried under vacuum, and characterized. In one set ofexperiments, 47.2 mg of L-malic acid salt former were dissolved in 1.0mL of acetone to obtain a clear solution. Added stepwise several spatulatips of solid SP196-FD-P1 until light suspension formed, sonicatedsuspension for 1 min, and obtained thicker suspension. Equilibratedsuspension with temperature cycling (holding for 1 h at 20° C., heatingin 1 h to 30° C., holding for 1 h at 30° C., cooling in 1 h to 20° C.,repeating) for 2 d. Recovered solid by filter centrifugation (0.2-μmPTFE membrane) to yield Form MLA-P4 (sample SP196-MLA-P4).

The FT-Raman spectrum of the scale-up sample SP196-MLA-P4 is shown inFIG. 52.

The XRPD pattern (FIG. 51) confirms the crystallinity of the material.The pattern does not correspond to any known pattern of the free drug.

The ¹H-NMR spectrum (FIG. 80) agrees with the structure of the freedrug, a L-malic acid salt former content of ˜1.0-1.2 eq., and no solventcontributions.

The elemental composition analysis complies with a 1:2 ratio of freedrug to salt former with ˜0.6 wt % H₂O (˜0.2 eq.), in agreement with theTG-FTIR and NMR results.

The TG-FTIR thermogram (FIG. 55) shows the loss of ˜0.6 wt % H₂O from50° C. to 140° C. and decomposition at temperatures T>140° C. The samplelikely corresponds to an anhydrous form and not a hydrate, as the smallamount of water is likely unbound.

The DSC thermogram (FIG. 53) shows several endothermic and exothermicevents starting at about 92° C.

The DVS isotherm (FIG. 54) shows a reversible mass loss of ˜2.5 wt %upon decreasing the relative humidity from 50% r.h. to 0%. Equilibriumwas reached at 0% r.h. Upon increasing the relative humidity from 50%r.h. to 95% r.h. a sudden mass increase of ˜6.4 wt % is observed between˜52% and 62% r.h., followed by a more gradual mass increase just above62% r.h. and then again an increase in the rate up to 95% r.h. (totalmass increase of ˜46.6 wt % from 50% r.h. to 95% r.h.). No equilibriumwas reached at 95% r.h. Upon decreasing the relative humidity from 95%r.h. to 50% r.h., a gradual mass loss occurred and the final massremained ˜4.2 wt % above the starting mass.

The mass increase of ˜17.6 wt % from 50% to 85% r.h. indicates that FormMLA-P4 is very hygroscopic.

The FT-Raman spectrum of the material after the DVS measurementcorresponds to the spectrum of the material before the DVS measurement.

Example 34. Preparation and Characterization of Form SUC-P3

Form SUC-P3 (e.g., sample SP196-SUC-P3) was prepared by combiningconcentrated solutions of succinic acid (salt former) and of compound 1(flee drug) in acetone. The solvent was partially evaporated under N₂flow. After spontaneous precipitation of a crystalline solid, thesuspension was equilibrated between 40° C. and 20° C. overnight. Thesolid material was recovered, dried under vacuum, and characterized. Inone set of experiments, 28.2 mg of succinic acid were dissolved in 1.2mL of acetone to obtain a clear solution. Added 9.6 mL of SP196-FD-stocksolution (1:1 ratio of FD to sf) to obtain a light yellow solution.Stirred solution at r.t. and after 2 h observed yellow suspension.Partially evaporated solvent under N₂ flow, sonicated suspension for 5min, and added 0.5 mL of acetone. Equilibrated suspension withtemperature cycling (holding for 1 h at 20° C., heating in 1 h to 30°C., holding for 1 h at 30° C., cooling in 1 h to 20° C., repeating)overnight. Recovered solid by filter centrifugation (0.2-μm PTFEmembrane) to yield Form SUC-P3 (sample SP196-SUC-P3).

The FT-Raman spectrum is shown in FIG. 57.

The XRPD pattern (FIG. 56) is very similar to the pattern of sampleSP196-MLA-P3. The pattern does not correspond to any known pattern ofthe free drug.

The ¹H-NMR spectrum (FIG. 81) agrees with the structure of a succinateof compound 1. The sample contains ˜0.3 eq. succinic acid salt formerand <0.01 eq. acetone solvent residue.

The TG-FTIR thermogram (FIG. 59) shows no mass loss from 50° C. to 180°C. and decomposition at temperatures T>180° C.

The DSC thermogram (FIG. 58) shows a sharp endothermic event with a peakat T_(max)=219.2° C. (ΔH=102.7 J/g), likely corresponding to melting,and no further event up to 250° C. The peak maximum is shifted comparedto the DSC thermogram of sample SP196-MLA-P3 (peak at T_(max)=212.3° C.)by ˜7° C.

The similar XRPD patterns of the SP196-MLA-P3 and SP196-SUC-P3 samplesat first suggested that both correspond not to salts but rather to oneand the same form of the free drug. However, the difference between thepeak maxima in the DSC thermograms indicates that these two samplesindeed correspond to two different salt forms with nearly identicallattice structures. The similar structures of the L-malic acid andsuccinic acid salt formers can maybe provide an explanation for thesimilarity of the XRPD patterns.

Example 35. Preparation and Characterization of Form SUC-P4

Form SUC-P4 (e.g., sample SP196-SUC-P4) was prepared by combiningconcentrated solutions of succinic acid (salt former) and of compound 1(free drug) in MeCN. Spontaneous precipitation of a crystalline solidoccurred. The suspension was equilibrated for 2 h. The solid materialwas recovered, dried under vacuum, and characterized. In one set ofexperiments, 102.1 mg of compound 1 (sample SP196-FD-P1) were dissolvedin 13.0 mL of MeCN, and the solution was filtered through 0.2-μm PTFEmembrane to obtain a clear solution. Dissolved 28.0 mg of succinic acidsalt former in 4.6 mL of MeCN and filtered solution through 0.2-μm PTFEmembrane. Combined the two solutions and sonicated solution for 1 h.Solution remained clear. Stirred solution at r.t. and after 1 h observedlight yellow suspension. Equilibrated suspension for 2 h; recoveredsolid by vacuum filtration (P4 pore size) to yield Form SUC-P4 (sampleSP196-SUC-P4).

The FT-Raman spectrum of the scale-up sample SP196-SUC-P4 is shown inFIG. 61.

The XRPD pattern of SP196-SUC-P4 (FIG. 60) confirms the crystallinity ofthe material. The pattern does not correspond to any known pattern ofthe free drug.

The ¹H-NMR spectrum of SP196-SUC-P4 (FIG. 82) agrees with the structureof a succinate of compound 1. The sample contains ˜0.45 eq. succinicacid salt former and ˜0.24 eq. MeCN solvent residues.

The TG-FTIR thermogram of SP196-SUC-P4 (data not shown) shows thegradual loss of ˜2.1 wt % H₂O and MeCN from 25° C. to 150° C. Most ofthis loss, however, occurs before or at the boiling point of thesolvents. Thus, the solvent content is likely due to unbound surfacewater/solvent. To confirm this hypothesis, the sample was dried undervacuum at r.t. and re-analyzed (as sample SUC-P4a) by XRPD and TG-FTIR.The XRPD pattern (data not shown) is unchanged.

The TG-FTIR thermogram of this dried sample SP196-SUC-P4a (FIG. 64)shows no significant mass loss from 25° C. to 170° C. and decompositionat temperatures T>170° C. Thus, this sample likely corresponds to ananhydrous form.

The elemental composition analysis (sample SP196-SUC-P4a) complies witha 1:0.5 ratio of free drug to salt former (Table 75).

TABLE 75 Elemental analysis results of SP196-SUC-P4a. % C % H % N % O ΣSP196-SUC-P4a (experimental) 65.3 5.8 12.0 16.4 99.5 SP196-SUC-P4a 65.65.9 12.0 16.5 100.0 (exp., normalized to 100%) C₂₄H₂₆N₄O₃, C₄H₄O₄ 62.76.0 10.4 20.9 100.0 (theoretical 1:1 salt) difference (exp. (norm.) —theo.) 2.9^(a) −0.1 1.6^(a) −4.4^(a) — C₂₄H₂₆N₄O₃, 0.5 × C₄H₄O₄ 65.6 6.111.8 16.5 100.0 (theoretical 1:0.5 salt) difference (exp. (norm) —theo.) 0.0 −0.2 0.2 0.0 — ^(a)Differences that exceed a measurementerror of ±0 3%.

Thus, the material of SUC-P4/P4a likely corresponds to an anhydroushemi-succinate salt of compound 1 (1:0.5 ratio of free drug to saltformer).

The DSC thermogram (FIG. 62) shows a small endothermic event with a peakat T_(max)=169.1° C. (ΔH=6.7 J/g) and a larger endothermic event withtwo peaks at T_(max)=212.2° C. and T_(max)=215.4° C. (total ΔH=92.6J/g), and no further event up to 250° C. The melting point of freesuccinic acid salt former is at about 184° C.

The DVS isotherm (FIG. 63) shows a reversible mass loss of ˜0.6 wt %upon decreasing the relative humidity from 50% r.h. to 0%. Equilibriumwas reached at 0% r.h. Upon increasing the relative humidity from 50%r.h. to 95% r.h. a sudden mass increase of ˜1.6 wt % is observed between50% and 60% r.h., afterwards a more gradual mass increase of ˜2.6 wt %between 60% and 95% r.h. (total mass increase of ˜4.2 wt % from 50% r.h.to 95% r.h.). No equilibrium was reached at 95% r.h. Upon decreasing therelative humidity from 95% r.h. to 50% r.h., a gradual mass loss of ˜2.1wt % occurred between 95% r.h. and 60% r.h., and a more sudden mass lossof ˜2.0 wt % between 60% r.h. and 50% r.h. The final mass remained ˜0.1wt % above the starting mass.

The mass increase of ˜2.5 wt % from 50% to 85% r.h. indicates that FormSUC-P4 is hygroscopic.

The FT-Raman spectrum of the material after the DVS measurementcorresponds to the spectrum of the material before the DVS measurement.

Example 36. Preparation and Characterization of Form SUC-P5

Form SUC-P5 (e.g., SUC-P5 Sample 1) was prepared by combining hotsolutions of succinic acid (salt former) and of compound 1 (free drug)in EtOAc, followed by slowly cooling to room temperature. Spontaneousprecipitation of a crystalline solid occurred at 50° C. The suspensionwas equilibrated for 1 h. The solid material was recovered, dried undervacuum, and characterized. In scale-up experiment, form SUC-P5 (e.g.,SUC-P5 Sample 1) was prepared by mixing the hot solutions of succinicacid (salt former) and of compound 1 (free drug) in EtOAc at about 70°C., followed by cooling to 65° C. and addition of slurry of seeds(SUC-P5 Sample 1) in EtOAc. The mixture was then stirred at 55-65° C.for 1 hour and then slowly cooled to room temperature and the suspensionwas equilibrated for 16 h. The solid material was recovered, dried undervacuum, and characterized.

The XRPD pattern of SUC-P5 (three different batches SUC-P5 Sample 1,SUC-P5 Sample 2, SUC-P5 Sample 3) (FIG. 87) confirms the crystallinityof the material. The pattern does not correspond to any known pattern ofthe free drug.

The ¹H-NMR spectrum of SUC-P5 Sample 1 (FIG. 89) agrees with thestructure of a succinate of compound 1. The sample contains ˜0.5 eq.succinic acid salt former and ˜0.1 eq. EtOAc solvent residues. The¹H-NMR spectrum of dried sample SUC-P5 Sample 1 shows the loss of thesignificant amount of EtOAc.

The DSC thermogram (FIG. 88) shows an endothermic event with a peak at207-208° C., with an approximately 7-8% weight loss up to that point. Nofurther event occurred to 300° C. The melting point of free succinicacid salt former is at about 184° C.

Example 37. Preparation and Characterization of Form MLE-P4

The FT-Raman spectrum of the salt scale-up sample SP196-MLE-P4 is shownin FIG. 66. The sample could contain a small amount of free maleic acidsalt former. In one set of experiments, 106.2 mg of maleic acid saltformer were dissolved in 1.0 mL of MeCN to obtain a clear solution.Added stepwise several spatula tips of solid compound 1 (sampleSP196-FD-P1) until light suspension formed. Sonicated suspension for 1min to obtain a thicker suspension. Equilibrated suspension withtemperature cycling (holding for 1 h at 20° C., heating in 1 h to 30°C., holding for 1 h at 30° C., cooling in 1 h to 20° C., repeating) for2 d. Recovered solid by filter centrifugation (0.2-μm PTFE membrane) toyield Form MLE-P4 (sample SP196-MLE-P4).

The XRPD pattern (FIG. 65) confirms the crystallinity of the material.The pattern does not correspond to any known pattern of the compound 1free drug. The sample could contain a small amount of free maleic acidsalt former.

The ¹H-NMR spectrum (FIG. 83) agrees with the structure of a maleate ofcompound 1 (maleic acid salt former content: ˜1.7 eq.; no solventcontent).

The TG-FTIR thermogram (FIG. 68) shows no mass loss from 25° C. to 120°C., the loss of ˜16.3 wt % (˜0.7 eq.) maleic acid (with some water) from120° C. to 250° C. and decomposition at temperatures T>250° C. Thus, thesample likely corresponds to an anhydrous form with low thermalstability.

The DSC thermogram (FIG. 67) shows a sharp endotherm with a peak atT_(max)=112.8° C. (ΔH≈55.5 J/g), followed by further endothermic eventswith a second significant peak at T_(max)=139.9° C. (total ΔH=51.3 J/g).Decomposition likely starts at T>145° C. The free maleic acid saltformer decomposes before melting at about 135° C.

Example 38. Preparation and Characterization of Form MLE-P6

Form MLE-P6 was prepared according to the following method. In a 25 mlconical flask, compound 1 (100 mg) was dissolved in acetone at 50-55°C., and maleic acid (30 mg) was added to the solution. The solutionbecomes clear by shaking at 50-55° C. for 5 min. The solution wasquickly filtered through a filter paper (e.g., in a second) into a clean25 ml conical flask and left undisturbed at ambient temperature withvery slight evaporation. The sharp needles separated were filtered anddried by passing air and then under high vacuum for 1 hour.

The melting point Form MLE-P6 was about 140-150° C.

¹HNMR (CDCl₃): δ 8.37 (d, 1H, J=3.0 Hz), 8.28 (s, 1H), 7.55 (d, 1H,J=3.0 Hz), 7.28-7.15 (m, 4H), 6.29 (bs, 1H), 6.26 (s, 1H), 4.44-4.31 (m,3H), 3.40-3.28 (m, 9H), 2.88-2.81 (m, 2H), 2.08 (s, 1.5H), 1.34 (t, 3H,J=6.9 Hz) ppm.

Example 39. Preparation and Characterization of Tartrate Salt

The tartrate salt of compound 1 was prepared according to the followingmethod. In a 25 ml conical flask compound 1 (418 mg) was dissolved inacetone (15 ml) at about 50-55° C., and tartaric acid (150 mg, 1.0equivalent) was added to the solution. The solution was heated withshaking at about 50-55° C. for 10 min to dissolve all solids. The hotsolution was quickly filtered through a filter paper in to a clean 25 mlconical flask and left undisturbed at ambient temperature with veryslight evaporation. The resulting rod-shaped crystals were filtered,dried by passing air, and then subject to high vacuum for 1 hour.

The melting point of the tartrate salt was about 140-200° C.(decomposition).

¹HNMR (DMSO-d₆): δ8.41 (d, 1-t, J=3.3 Hz), 8.32 (s, 1H), 7.59 (d, 1H,J=3.0 Hz), 7.32-7.18 (m, 4H), 6.29 (bd, 1H, J=6.6 Hz), 5.14 (bs, 111),4.83-4.41 (m, 5H), 3.44-3.30 (m, 9H), 2.92-2.85 (m, 2H), 2.12 (s, 2H),1.38 (t, 3H, J=6.9 Hz) ppm.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A hemi-succinate salt of the crystalline Form SUC-P5 of compound 1:


2. The crystalline Form SUC-P5 of claim 1, wherein the crystalline Form SUC-P5 is substantially free of impurities.
 3. The crystalline Form SUC-P5 of claim 1, wherein the crystalline Form SUC-P5 is substantially free of amorphous compound
 1. 4. The crystalline Form SUC-P5 of claim 1, wherein the crystalline Form SUC-P5 has two or more peaks in its x-ray powder diffraction (XRPD) pattern selected from those in the following table: Angle 2-Theta ° 7.4 15.6 16.5 18.5 22.2.


5. The crystalline Form SUC-P5 of claim 1, wherein the crystalline Form SUC-P5 has four or more peaks in its XRPD pattern selected from those in the following table: Angle 2-Theta ° 7.4 8.3 10.5 11.7 13.2 15.6 16.5 18.5 22.2.


6. The crystalline Form SUC-P5 of claim 1, wherein the crystalline Form SUC-P5 is characterized by a differential scanning calorimetry (DSC) thermogram with an endotherm having a peak temperature (T_(max)) of about 207° C.
 7. The crystalline Form SUC-P5 of claim 1, wherein the crystalline Form SUC-P5 is characterized by a DSC thermogram with a ΔH of about 6.7 J/g or about 92.6 J/g.
 8. A pharmaceutical composition comprising the crystalline form SUC-P5 of claim 1, and optionally a pharmaceutically acceptable excipient.
 9. The pharmaceutical composition of claim 8, wherein the crystalline form SUC-P5 is of a therapeutically effective amount.
 10. A method of treating an anxiety disorder or depression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim
 8. 11. The method of claim 10, wherein the depression is major depressive disorder (MDD), bipolar disorder (BD), atypical depression, melancholic depression, psychotic major depression, catatonic depression, postpartum depression, seasonal affective disorder, dysthymia, a depressive disorder not otherwise specified (DD-NOS), or a substance induced mood disorder.
 12. The method of claim 10, wherein the anxiety disorder is panic disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), substance-induced anxiety disorder, acute stress disorder (ASD), irritable bowel syndrome, or fibromyalgia.
 13. The method of claim 10, wherein the anxiety disorder is a phobia.
 14. The method of claim 10, wherein the phobia is social phobia, agoraphobia, or animal phobia.
 15. The method of claim 10, wherein the subject is a human. 